RESUMEN

Zinc finger protein 180 (ZNF180) is a multifunctional protein that interacts with nucleic acids and regulates various cellular processes; however, the function of ZNF180 in colorectal cancer (CRC) remains unclear. The present study investigated the role and function of ZNF180 in CRC, and aimed to reveal the underlying molecular mechanism. The results revealed that ZNF180 was downregulated in CRC tissues and was associated with a good prognosis in patients with CRC. Additionally, the expression of ZNF180 was downregulated by methylation in CRC. In vivo and in vitro experiments revealed that ZNF180 overexpression was functionally associated with the inhibition of cell proliferation and the induction of apoptosis. Mechanistically, chromatin immunoprecipitation­PCR and luciferase assays demonstrated that ZNF180 markedly regulated the transcriptional activity of methyltransferase 14, N6­adenosine­methyltransferase non­catalytic subunit (METTL14) by directly binding to and activating its promoter region. Simultaneous overexpression of ZNF180 and knockdown of METTL14 indicated that the reduction of METTL14 could suppress the effects of ZNF180 on the induction of apoptosis. Clinically, the present study observed a significant positive correlation between ZNF180 and METTL14 expression levels, and low expression of ZNF180 and METTL14 predicted a poor prognosis in CRC. Overall, these findings revealed a novel mechanism by which the ZNF180/METTL14 axis may modulate apoptosis and cell proliferation in CRC. This evidence suggests that this axis may serve as a prognostic biomarker and therapeutic target in patients with CRC.

Asunto(s)

Apoptosis , Proliferación Celular , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Metiltransferasas , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Apoptosis/genética , Proliferación Celular/genética , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Línea Celular Tumoral , Animales , Activación Transcripcional , Ratones , Regiones Promotoras Genéticas , Anciano , Regulación hacia Abajo , Metilación de ADN

RESUMEN

Zinc finger protein 667 (ZNF667, also referred as Mipu1), a widely expressed KRAB/C2H2­type zinc finger transcription factor, can protect against hypoxic­ischemic myocardial injury. Pro­angiogenesis is regarded as a promising strategy for the treatment of acute myocardial infarction (AMI). However, whether ZNF667 is involved in the angiogenesis following AMI remains to be elucidated. The present study reported that the expression of ZNF667 in CD31­positive endothelial cells (ECs) was upregulated in the heart of AMI mice. Hypoxic challenge (1% oxygen) promoted the mRNA and protein expression of ZNF667 in the human umbilical vein endothelial cells (HUVECs) in a time­dependent manner. Moreover, ZNF667 promoted hypoxia­induced invasion and tube formation of HUVECs. Mechanically, ZNF667 could directly bind to the promoter of anti­angiogenic gene VASH1 and inhibit its expression. Consequently, VASH1 overexpression abolished hypoxic challenge or ZNF667 overexpression­induced invasion and tube formation of HUVECs. Further bioinformatic analyses suggested that overexpression of ZNF667 or knockdown of VASH1­induced differentially expressed genes in HUVECs were greatly enriched in the Wnt signaling pathway (DAAM1, LEF1, RAC2, FRAT1, NFATc2 and WNT5A). Together, these data suggested that ZNF667 facilitates myocardial ischemia­driven angiogenesis through transcriptional repression of VASH1 and regulation of Wnt signaling pathway.

Asunto(s)

Proteínas Portadoras , Proteínas de Ciclo Celular , Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Isquemia Miocárdica , Proteínas Oncogénicas , Vía de Señalización Wnt , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular/genética , Enfermedad de la Arteria Coronaria/metabolismo , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones , Proteínas de Microfilamentos/genética , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Neovascularización Patológica/metabolismo , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Proteínas de Unión al GTP rho