RESUMEN

Histone deacetylase 5 (HDAC5) is an enzyme that deacetylates lysine residues on the N-terminal of histones and other proteins. It has been reported that HDAC5 deacetylates p53, the critical factor regulating cell cycle, in response to cellular stress, but the transcriptional products haven't been identified. Herein, we used p53 signaling pathway qPCR-chip to determine how HDAC5-mediated deacetylation of p53 affects cell cycle. However, validation using immunoblotting analysis revealed that acetylation of p53 at K120 impacted little to the expression of the genes identified using the qPCR-chip, indicating HDAC5 might deacetylate some other proteins to facilitate cell cycle via transactivating the differentially expressed genes determined by the qPCR-chip. The subsequent assays demonstrated that HDAC5 deacetylated c-Myc at K143 and K157 to facilitate the transactivation of CDK1, CDK4, and CDC25C, promoting cell cycle progression of hepatocellular carcinoma (HCC). This study shows that HDAC5 plays important roles in modulating deacetylation of c-Myc and regulating cell cycle progression, and it proves that LMK-235, the inhibitor targeting HDAC5 potentially serves as a drug for combating HCC via promoting acetylation of c-Myc at K143 and K157.

RESUMEN

OBJECTIVE: The E3 ubiquitin ligase is well recognized as a significant contributor to glioblastoma (GBM) progression and has promise as a prospective therapeutic target. This study explores the contribution of E3 ubiquitin ligase RNF122 in the GBM progression and the related molecular mechanisms. METHODS: RNF122 expression levels were evaluated using qRT-PCR, WB, and IHC, while functional assays besides animal experiments were used to assess RNF122's effect on GBM progression. We also tested the RNF122 impact on JAK2/STAT3/c-Myc signaling using WB. RESULTS: RNF122 was upregulated in GBM and correlated to the advanced stage and poor clinical outcomes, representing an independent prognostic factor. Based on functional assays, RNF122 promotes GBM growth and cell cycle, which was validated further in subsequent analyses by JAK2/STAT3/c-Myc pathway activation. Moreover, JAK2/STAT3 signaling pathway inhibitor WP1066 can weaken the effect of overexpression RNF122 on promoting GBM progression. CONCLUSION: Our results revealed that RNF122 caused an aggressive phenotype to GBM and was a poor prognosticator; thus, targeting RNF122 may be effectual in GBM treatment.

Asunto(s)

Neoplasias Encefálicas , Glioblastoma , Janus Quinasa 2 , Proteínas Proto-Oncogénicas c-myc , Factor de Transcripción STAT3 , Transducción de Señal , Ubiquitina-Proteína Ligasas , Humanos , Glioblastoma/metabolismo , Glioblastoma/patología , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Masculino , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Femenino , Animales , Línea Celular Tumoral , Ratones Desnudos , Persona de Mediana Edad , Ratones , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Ratones Endogámicos BALB C , Péptidos y Proteínas de Señalización Intracelular

RESUMEN

Proliferation of renal tubular epithelial cells (TEC) is essential for restoring tubular integrity and thereby to support renal functional recovery from kidney ischemia/reperfusion (KI/R) injury. Activation of transcriptional factor c-Myc promotes TEC proliferation following KI/R; however, the mechanism regarding c-Myc activation in TEC is incompletely known. Heat shock protein A12A (HSPA12A) is an atypic member of HSP70 family. In this study, we found that KI/R decreased HSPA12A expression in mouse kidneys and TEC, while ablation of HSPA12A in mice impaired TEC proliferation and renal functional recovery following KI/R. Gain-of-functional studies demonstrated that HSPA12A promoted TEC proliferation upon hypoxia/reoxygenation (H/R) through directly interacting with c-Myc and enhancing its nuclear localization to upregulate expression of its target genes related to TEC proliferation. Notably, c-Myc was lactylated in TEC after H/R, and this lactylation was enhanced by HSPA12A overexpression. Importantly, inhibition of c-Myc lactylation attenuated the HSPA12A-induced increases of c-Myc nuclear localization, proliferation-related gene expression, and TEC proliferation. Further experiments revealed that HSPA12A promoted c-Myc lactylation via increasing the glycolysis-derived lactate generation in a Hif1α-dependent manner. The results unraveled a role of HSPA12A in promoting TEC proliferation and facilitating renal recovery following KI/R, and this role of HSPA12A was achieved through increasing lactylation-mediated c-Myc activation. Therefore, targeting HSPA12A in TEC might be a viable strategy to promote renal functional recovery from KI/R injury in patients.

Asunto(s)

Proliferación Celular , Células Epiteliales , Proteínas HSP70 de Choque Térmico , Túbulos Renales , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-myc , Daño por Reperfusión , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP70 de Choque Térmico/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Ratones , Células Epiteliales/metabolismo , Células Epiteliales/patología , Túbulos Renales/metabolismo , Túbulos Renales/patología , Masculino , Humanos , Riñón/metabolismo , Riñón/patología

RESUMEN

Breast cancer progression and metastasis are closely connected to changes in glucose and glutamine metabolism. While Novel (nua) kinase family 1 (NUAK1) and Novel (nua) kinase family 2 (NUAK2), which are two members of the AMPK-related kinases, have been associated with breast tumorigenesis, their role in the metabolic reprogramming that occurs during breast cancer progression remains unclear. Our research uncovers that NUAKs expression is significantly higher in breast cancer tissues and cell lines, and it is positively related to glycolysis, the pentose phosphate pathway (PPP), glutamine metabolism, and a poor prognosis for breast cancer patients. We show that NUAKs significantly increase metabolic reprogramming, including aerobic glycolysis, PPP, and glutamine metabolism in triple negative breast cancer subtypes but only induce aerobic glycolysis and PPP in luminal breast cancer subtypes to meet the anabolic demands of rapidly dividing breast cancer cells. In contrast, the depletion of NUAKs has the opposite effect. Mechanistic insights reveal that NUAKs activate mammalian target of rapamycin (mTOR) signaling, which in turn upregulates the c-Myc transcription factor, a crucial regulator of glucose and glutamine metabolic gene expression. Moreover, we demonstrate that NUAKs enhance mTOR/c-Myc signaling pathways, leading to increased glucose and glutamine reprogramming, which supports rapid cell proliferation and metastatic potential in breast cancer cells. Importantly, pretreating breast cancer cells with mTOR inhibitors blocked the metabolic reprogramming and tumor-promoting effect of NUAK1/2. Therefore, targeting NUAKs may represent a novel therapeutic strategy for the treatment of breast cancer.

RESUMEN

CD8 + T cells have critical roles in tumor control, but a range of factors in their microenvironment such as low pH can suppress their function. Here, we demonstrate that acidity restricts T-cell expansion mainly through impairing IL-2 responsiveness, lowers cytokine secretion upon re-activation, and reduces the cytolytic capacity of CD8 + T cells expressing low-affinity TCR. We further find decreased mTORC1 signaling activity and c-Myc levels at low pH. Mechanistically, nuclear/cytoplasmic acidification is linked to mTORC1 suppression in a Rheb-, Akt/TSC2/PRAS40-, GATOR1- and Lkb1/AMPK-independent manner, while c-Myc levels drop due to both decreased transcription and higher levels of proteasome-mediated degradation. In addition, lower intracellular levels of glutamine, glutamate, and aspartate, as well as elevated proline levels are observed with no apparent impact on mTORC1 signaling or c-Myc levels. Overall, we suggest that, due to the broad impact of acidity on CD8 + T cells, multiple interventions will be required to restore T-cell function unless intracellular pH is effectively controlled.

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BACKGROUND: Macrophage-based cell therapy is promising in solid tumors, but the efficient acquisition of macrophages remains a challenge. Induced pluripotent stem cell (iPSC)-induced macrophages are a valuable source, but time-consuming and costly. The application of reprogramming technologies allows for the generation of macrophages from somatic cells, thereby facilitating the advancement of cell-based therapies for numerous malignant diseases. METHODS: The composition of CD45+ myeloid-like cell complex (MCC) and induced macrophage (iMac) were analyzed by flow cytometry and single-cell RNA sequencing. The engraftment capacity of CD45+ MCC was evaluated by two transplantation assays. Regulation of c-Myc on MafB was evaluated by ChIP-qPCR and promoter reporter and dual luciferase assays. The phenotype and phagocytosis of iMac were explored by flow cytometry and immunofluorescence. Leukemia, breast cancer, and patient-derived tumor xenograft models were used to explore the anti-tumor function of iMac. RESULTS: Here we report on the establishment of a novel methodology allowing for reprogramming fibroblasts into functional macrophages with phagocytic activity by c-Myc overexpression. Fibroblasts with ectopic expression of c-Myc in iPSC medium rapidly generated CD45+ MCC intermediates with engraftment capacity as well as the repopulation of distinct hematopoietic compartments. MCC intermediates were stably maintained in iPSC medium and continuously generated functional and highly pure iMac just by M-CSF cytokine stimulation. Single-cell transcriptomic analysis of MCC intermediates revealed that c-Myc up-regulated the expression of MafB, a major regulator of macrophage differentiation, to promote macrophage differentiation. Characterization of the iMac activity showed NF-κB signaling activation and a pro-inflammatory phenotype. iMac cells displayed significantly increased in vivo persistence and inhibition of tumor progression in leukemia, breast cancer, and patient-derived tumor xenograft models. CONCLUSIONS: Our findings demonstrate that c-Myc alone is enough to reprogram fibroblasts into functional macrophages, supporting that c-Myc reprogramming strategy of fibroblasts can help circumvent long-standing obstacles to gaining "off-the-shelf" macrophages for anti-cancer immunotherapy.

Asunto(s)

Reprogramación Celular , Fibroblastos , Macrófagos , Proteínas Proto-Oncogénicas c-myc , Macrófagos/metabolismo , Macrófagos/citología , Animales , Humanos , Ratones , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Fibroblastos/metabolismo , Fibroblastos/citología , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Femenino

RESUMEN

The impact of Sodium Houttuyniae (SH) on lipopolysaccharide (LPS)-induced ALI has been investigated extensively. However, it remains ambiguous whether ferroptosis participates in this process. This study aimed to find out the impacts and probable mechanisms of SH on LPS-induced ferroptosis. A rat ALI model and type II alveolar epithelial (ATII) cell injury model were treated with LPS. Enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, and Giemsa staining were executed to ascertain the effects of SH on LPS-induced ALI. Moreover, Transmission electron microscopy, Cell Counting Kit-8 (CCK8), ferrous iron colorimetric assay kit, Immunohistochemistry, Immunofluorescence, Reactive oxygen species assay kit, western blotting (Wb), and qRT-PCR examined the impacts of SH on LPS-induced ferroptosis and ferroptosis-related pathways. Theresults found that by using SH treatment, there was a remarkable attenuation of ALI by suppressing LPS-induced ferroptosis. Ferroptosis was demonstrated by a decline in the levels of glutathione peroxidase 4 (GPX4), FTH1, and glutathione (GSH) and a surge in the accumulation of malondialdehyde (MDA), reactive oxygen species (ROS), NOX1, NCOA4, and Fe2+, and disruption of mitochondrial structure, which were reversed by SH treatment. SH suppressed ferroptosis by regulating TRAF6-c-Myc in ALI rats and rat ATII cells. The results suggested that SH treatment attenuated LPS-induced ALI by repressing ferroptosis, and the mode of action can be linked to regulating the TRAF6-c-Myc signaling pathway in vivo and in vitro.

Asunto(s)

Lesión Pulmonar Aguda , Medicamentos Herbarios Chinos , Ferroptosis , Lipopolisacáridos , Proteínas Proto-Oncogénicas c-myc , Transducción de Señal , Factor 6 Asociado a Receptor de TNF , Animales , Masculino , Ratas , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ferroptosis/efectos de los fármacos , Lipopolisacáridos/toxicidad , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/genética

RESUMEN

BACKGROUND: So many risk factors for mobilization failure have been described so far. We aimed to identify the risk factors and search the possible effects of bone marrow fibrosis (BMF), CD56, c-myc, and cyclinD1 expression on mobilization. METHODS: We evaluated 189 patients with MM who were admitted for stem cell mobilization before autologous stem cell transplantation (ASCT) between 2015 and June 2021. Clinical, laboratory, treatment features, and survival outcomes were compared in patients who were successfully mobilized and who were not. RESULTS: Mobilization failure rate was 11.1 % (21) in our study group. Male gender, mobilization with only G-CSF, history of previous ASCT, lenalidomide exposure, and 2 lines of chemotherapy before stem cell mobilization were observed more commonly in mobilization failure group. There is no relationship between mobilization failure and BMF, CD56, c-myc, and cyclin D1 expression status in patients who received either only G-CSF or G-CSF+ chemotherapy for mobilization. Overall survival (OS) was not different in groups of patients who were successfully mobilized and who were not. Neutrophil engraftment was faster in patients who were transfused > 5 × 106/kg stem cells (p = 0.015). ECOG performance status (p = 0.004), c-myc expression (p = 0.005), lenalidomide therapy before mobilization (p = 0.032), and mobilization with G-CSF+chemotherapy was found to be predictive factors for OS. CONCLUSION: Even though we could not find any predictive value of CD56, c-myc, and cyclin D1 expression on mobilization, c-myc was found to be associated with low OS. Further studies with large and homogenous study population would be more informative.

RESUMEN

Purpose: The clinical benefits of poly(ADP-ribose) polymerase (PARP) inhibitors are limited to triple-negative breast cancer (TNBC) with BRCA deficiency due to primary and acquired resistance. Thus, there is a pressing need to develop alternative treatment regimens to target BRCA-mutated TNBC tumors that are resistant to PARP inhibition. Similar to PARP, poly(ADP-ribose) glycohydrolase (PARG) plays a role in DNA replication and repair. However, there are conflicting reports on the vulnerability of BRCA1-deficient tumor cells to PARG inhibition. This study aims to investigate the synergistically lethal effect of the PARG inhibitor COH34 and the ubiquitin-specific protease (USP) 14 inhibitor IU1-248 and the underlying mechanisms in BRCA1-mutant, PARP inhibitor-resistant TNBC cells. Methods: The cytotoxicity of PARG inhibition alone or in combination with USP14 inhibition in the BRCA-mutant, PARP inhibitor-resistant TNBC cell lines, HCC1937 and SUM149PT, was analyzed using cell viability and proliferation assays and flow cytometry. The molecular mechanisms underlying the synergistic effects of IU1-248 and COH34 were evaluated by immunofluorescence staining, DNA repair reporter assays and Western blot analysis. Results: It was found that HCC1937 and SUM149PT cells exhibited moderate responsiveness to PARG inhibition alone. To the best of our knowledge, this research is the first to demonstrate that the combination of IU1-248 and COH34 produces synergistic effects against TNBC cells in the same setting. Mechanistically, the blockade of USP14 by IU1-248 was shown to increase DNA damage and promote error-prone non-homologous end joining (NHEJ), as evidenced by the accumulation of γH2AX and 53BP1 in the nucleus and the activation of a reporter assay. Additionally, it was demonstrated that the inhibition of NHEJ repair activity attenuates the synergistic effects of concomitant PARG and USP14 inhibition. IU1-248 promotes NHEJ repair through the downregulation of the expression of c-Myc. Conclusion: USP14 inhibition may be a plausible strategy for expanding the utility of PARG inhibitors in TNBC in BRCA-mutant, PARP inhibitor-resistant settings.

RESUMEN

BACKGROUND: Armadillo Repeat Containing X-Linked 1 (ARMCX1), a member of the ARM Repeat X-linked protein family, exerts inhibitory function in various tumors. However, its biological role in lung adenocarcinoma (LUAD) and the underlying molecular mechanisms require further exploration. METHODS: LUAD tissue microarrays and bioinformatic databases were used to evaluate the relationship between ARMCX1 and clinicopathological features. The influence of ARMCX1 on LUAD cell proliferation, migration, and invasion in vitro was determined by colony formation, CCK-8, EdU incorporation, cell cycle, wound healing, and Transwell assays. The impact of ARMCX1 on LUAD cell growth and metastasis in vivo was determined by subcutaneously transplanted tumor and pulmonary metastasis assays. Western blot, immunoprecipitation, immunofluorescence, cycloheximide, and proteasome inhibitor assays were finally conducted to explore the potential underlying molecular mechanisms. RESULTS: ARMCX1 expression was downregulated in clinical LUAD samples due to which patient prognoses were poor. Functional experiments indicated that ARMCX1 overexpression inhibited the growth and metastasis of LUAD cells in vitro and in vivo. The molecular mechanism suggested that ARMCX1 recruits the E3 ubiquitin ligase FBXW7 for mediating ubiquitinated degradation of c-Myc, suppressing its nuclear accumulation, and ultimately inactivating cell cycle and epithelial-mesenchymal transition (EMT) signals. CONCLUSION: ARMCX1 inhibits LUAD cell proliferation and metastasis by interacting with c-Myc and enhancing its ubiquitination and degradation. Consequently, it can act as a tumor suppressor in this disease. These results suggest that ARMCX1 is a potential target in the treatment of LUAD.

Asunto(s)

Adenocarcinoma del Pulmón , Proteína 7 que Contiene Repeticiones F-Box-WD , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-myc , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Animales , Ratones , Línea Celular Tumoral , Proliferación Celular , Proteolisis , Progresión de la Enfermedad , Movimiento Celular , Masculino , Ratones Desnudos , Femenino , Regulación Neoplásica de la Expresión Génica

RESUMEN

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.

RESUMEN

Lung cancer represents one of the most prevalent malignant neoplasms, commanding an alarming incidence and mortality rate globally. Non-small cell lung cancer (NSCLC), constituting approximately 80 %-90 % of all lung cancer cases, is the predominant pathological manifestation of this disease, with a disconcerting 5-year survival rate scarcely reaching 10 %. Extensive prior investigations have elucidated that the aberrant expression of X-ray repair cross-complementing gene 2 (XRCC2), a critical meiotic gene intricately involved in the DNA damage repair process, is intimately associated with tumorigenesis. Nevertheless, the precise roles and underlying mechanistic pathways of XRCC2 in NSCLC remain largely elusive. In the present study, we discerned an overexpression of XRCC2 within NSCLC patient tissues, particularly in high-grade samples, when juxtaposed with normal tissues. Targeted knockdown of XRCC2 notably impeded the proliferation of NSCLC both in vitro and in vivo. Comprehensive RNA sequencing and flow rescue assays unveiled that XRCC2 augments the proliferation of NSCLC cells through the down-regulation of FOS expression. Moreover, the c-Myc gene was definitively identified as an XRCC2 transcriptional factor by means of chromatin immunoprecipitation (ChIP) and luciferase reporter assays, whereby pharmacological attenuation of c-Myc expression, in conjunction with Doxorubicin, synergistically curtailed NSCLC cell growth both in vitro and in vivo. Collectively, our findings proffer critical insights into the novel c-Myc-XRCC2-FOS axis in promoting both proliferation and resistance to Doxorubicin in NSCLC cells, thereby extending a promising avenue for potential new diagnostic strategies and therapeutic interventions in NSCLC.

RESUMEN

The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.

RESUMEN

BACKGROUND: Glioblastoma (GBM) is a brain tumor with poor prognosis. Dexmedetomidine (Dex) regulates the biological behaviors of tumor cells to accelerate or decelerate cancer progression. OBJECTIVE: We investigated the effects of Dex on the migration, invasion, and glycolysis in GBM. METHODS: The concentration of Dex was determined using the cell counting kit-8 assay. The impacts of Dex on biological behaviors of GBM cells were assessed using Transwell assay, XF96 extracellular flux analysis, and western blot. The expression of c-Myc was examined using reverse transcription-quantitative polymerase chain reaction. The lactylation or stability of c-Myc was measured by western blot after immunoprecipitation or cycloheximide treatment. RESULTS: We found that Dex (200 nM) inhibited GBM cell viability, migration, invasion, and glycolysis. C-Myc was highly expressed in GBM cells and was decreased by Dex treatment. Moreover, Dex suppressed lactylated c-Myc levels via suppressing glycolysis, thereby reducing the protein stability of c-Myc. Sodium lactate treatment abrogated the effects of Dex on the biological behaviors of GBM cells. CONCLUSION: Dex suppressed the migration, invasion, and glycolysis of GBM cells via inhibiting lactylation of c-Myc and suppressing the c-Myc stability, suggesting that Dex may be a novel therapeutic drug for GBM treatment.

RESUMEN

Hepatocellular carcinoma (HCC) is the primary malignant tumor of the liver. c-Myc is one of the most common oncogenes in clinical settings, and amplified levels of c-Myc are frequently found in HCC. Histone deacetylase inhibitors (HDACi), such as Trichostatin A (TSA), hold enormous promise for the treatment of HCC. However, the potential and mechanism of TSA in the treatment of c-Myc-induced HCC are unclear. In this study, we investigated the effects of TSA treatment on a c-Myc-induced HCC model in mice. TSA treatment delayed the development of HCC, and liver function indicators such as ALT, AST, liver weight ratio, and spleen weight ratio demonstrated the effectiveness of TSA treatment. Oil red staining further demonstrated that TSA attenuated lipid accumulation in the HCC tissues of mice. Through mRNA sequencing, we identified that TSA mainly affected cell cycle and fatty acid degradation genes, with alcohol dehydrogenase 4 (ADH4) potentially being the core molecular downstream target. QPCR, immunohistochemistry, and western blot analysis revealed that ADH4 expression was repressed by c-Myc and restored after TSA treatment both in vitro and in vivo. Furthermore, we observed that the levels of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration increased after c-Myc transfection in liver cells but decreased after TSA intervention. The levels of phosphorylated protein kinase B (p-AKT) and p-mTOR were identified as targets regulated by TSA, and they governed the ADH4 expression and the downstream regulation of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration. Overall, our study suggests that TSA has a therapeutic effect on c-Myc-induced HCC through the AKT-mTOR-ADH4 pathway. These findings provide valuable insights into the potential treatment of HCC using TSA and shed light on the underlying molecular mechanisms involved.

Asunto(s)

Carcinoma Hepatocelular , Ácidos Hidroxámicos , Neoplasias Hepáticas , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas c-myc , Animales , Ratones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Alcohol Deshidrogenasa/metabolismo , Alcohol Deshidrogenasa/genética , Masculino , Progresión de la Enfermedad , Carcinogénesis/efectos de los fármacos , Línea Celular Tumoral , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos

RESUMEN

The antiapoptotic protein BCL2A1 is highly, but very heterogeneously expressed in Diffuse Large B-cell Lymphoma (DLBCL). Particularly in the context of resistance to current therapies, BCL2A1 appears to play an important role in protecting cancer cells from the induction of cell death. Reducing BCL2A1 levels may have therapeutic potential, however, no specific inhibitor is currently available. In this study, we hypothesized that the signaling network regulated by epigenetic readers may regulate the transcription of BCL2A1 and hence that inhibition of Bromodomain and Extra-Terminal (BET) proteins may reduce BCL2A1 expression thus leading to cell death in DLBCL cell lines. We found that the mechanisms of action of acetyl-lysine competitive BET inhibitors are different from those of proteolysis targeting chimeras (PROTACs) that induce the degradation of BET proteins. Both classes of BETi reduced the expression of BCL2A1 which coincided with a marked downregulation of c-MYC. Mechanistically, BET inhibition attenuated the constitutively active canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway and inhibited p65 activation. Furthermore, signal transducer of activated transcription (STAT) signaling was reduced by inhibiting BET proteins, targeting another pathway that is often constitutively active in DLBCL. Both pathways were also inhibited by the IκB kinase inhibitor TPCA-1, resulting in decreased BCL2A1 and c-MYC expression. Taken together, our study highlights a novel complex regulatory network that links BET proteins to both NFκB and STAT survival signaling pathways controlling both BCL2A1 and c-MYC expression in DLBCL.

Asunto(s)

Linfoma de Células B Grandes Difuso , FN-kappa B , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas c-myc , Transducción de Señal , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Línea Celular Tumoral , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proteínas que Contienen Bromodominio , Proteínas , Antígenos de Histocompatibilidad Menor

RESUMEN

c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3'UTR of c-MYC to specifically destabilize and promote the degradation of c-MYC transcripts. Interestingly, the engineered derivative outcompetes the endogenous overexpressed c-MYC mRNA, leading to reduced c-MYC mRNA and protein levels. The iron oxide nanocages (IO-nanocages) complexed with MYC-destabilizing constructs inhibited primary and metastatic tumors in mice bearing TNBC and significantly prolonged survival by degrading the c-MYC-STAT5A/B-PD-L1 complexes that drive c-MYC-positive TNBC. Taken together, we have described a novel therapy for c-MYC-driven TNBC and uncovered c-MYC-STAT5A/B-PD-L1 interaction as the target.

RESUMEN

c-MYC is one of the most important oncogenes, which is overexpressed in many cancers, and is highly related to development, metastasis, and drug resistance of cancers. The G4 structure in the promoter of c-MYC oncogene contributes a lot to the gene transcriptional mechanism. Small-molecule ligands binding to the c-MYC G4 appear to be a new class of anticancer agents. However, selective ligands for the c-MYC G4 over other G4s have been rarely reported. In this study, we reported a novel fluorescent ligand by migrating the benzene group on a carbazole-benzothiazolium scaffold, which was demonstrated to exhibit considerable specificity to the c-MYC G4, which was distinguished from other small-molecule ligands. The further cellular experiments suggested that this ligand may indeed target the promoter G4 and cause apparent transcriptional inhibition of the c-MYC oncogene instead of other G4-mediated oncogenes, which thereby resulted in cancer cell growth inhibition. Collectively, this study provided a good example for developing specific c-MYC G4 ligands, which may further develop into an effective anticancer agent that inhibit the c-MYC expression.

Asunto(s)

Antineoplásicos , Benzotiazoles , Carbazoles , Proliferación Celular , Colorantes Fluorescentes , G-Cuádruplex , Proteínas Proto-Oncogénicas c-myc , Carbazoles/química , Carbazoles/farmacología , G-Cuádruplex/efectos de los fármacos , Humanos , Ligandos , Benzotiazoles/química , Benzotiazoles/farmacología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/genética , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Relación Dosis-Respuesta a Droga , Benceno/química , Benceno/farmacología , Línea Celular Tumoral

RESUMEN

The number of breast cancer (BC) patients is increasing year by year, which is severely endangering to human life and health. c-Myc is a transcription factor, studies have shown that it is a very significant factor in tumor progression, but how it is regulated in BC is still not well understood. Here, we used the RIP microarray sequencing to confirm circXPO6, which had a high affinity with c-Myc and highly expressed in triple-negative breast cancer (TNBC) tissues and cells. CircXPO6 overexpression promoted tumor growth in vivo and in vitro. Furthermore, circXPO6 largely promoted the expression of genes related to glucose metabolism, such as GLUT1, HK2, and MCT4 in TNBC cells. Finally, high levels of circXPO6 expression were found to be closely associated with malignant pathological factors, such as tumor size, lymph node metastasis, TNM staging, and histopathological grading of TNBC. Mechanistically, circXPO6 interacted with c-Myc to prevent speckle-type POZ-mediated c-Myc ubiquitination and degradation, thus promoting TNBC progression. Through the regulation of c-Myc-mediated signal transduction, circXPO6 plays a key role in TNBC progresses. This discovery can provide new ideas for TNBC molecular targeted therapy.

RESUMEN

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by a complex pathogenesis involving various types of cells and cytokines. Among those, the pro-inflammatory cytokine IL-23/IL-17A axis plays a crucial role in the development and rapid progression of psoriasis. Phenformin, a derivative of metformin and a member of the biguanide class of drugs, exhibits superior anti-inflammatory and anti-tumor efficacy compared to metformin. However, the potential role of phenformin in anti-psoriatic skin inflammation has not been explored. METHODS: In this study, we utilized a mouse model of psoriasis and an in vitro model using human keratinocytes to investigate whether phenformin can suppress psoriasis-like inflammatory responses. RESULTS: Our results demonstrate that the topical application of phenformin significantly inhibited acute skin inflammatory responses in the psoriasis mouse model induced by imiquimod (IMQ). Additionally, phenformin suppressed the expression of psoriasis-related cytokines IL-17, IL-23, IL-8, and S100A8/S100A9 in an in vitro psoriatic keratinocyte model induced by IMQ. Furthermore, we found that IMQ-induced psoriatic skin and IMQ-treated keratinocytes exhibited high expression of the c-Myc gene, which was downregulated by phenformin. The c-Myc inhibitor JQ1 similarly inhibited the psoriatic inflammatory response and the expression of psoriasis-related cytokines in both in vitro and in vivo models. CONCLUSION: phenformin ameliorates the psoriasis-like inflammatory response by inhibiting c-Myc expression in keratinocytes, suggesting its potential as a topical drug for the treatment of psoriasis.