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Histone methylation plays crucial roles in regulating chromatin structure and gene transcription in epigenetic modifications. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is universally overexpressed in various diseases. LSD1 dysregulation is closely associated with cancer, viral infections, and neurodegenerative diseases, etc., making it a promising therapeutic target. Several LSD1 inhibitors and two small-molecule degraders (UM171 and BEA-17) have entered the clinical stage. LSD1 can remove methyl groups from histone 3 at lysine 4 or lysine 9 (H3K4 or H3K9), resulting in either transcription repression or activation. While the roles of LSD1 in transcriptional regulation are well-established, studies have revealed that LSD1 can also be dynamically regulated by other factors. For example, the expression or activity of LSD1 can be regulated by many proteins that form transcriptional corepressor complexes with LSD1. Moreover, some post-transcriptional modifications and cellular metabolites can also regulate LSD1 expression or its demethylase activity. Therefore, in this review, we will systematically summarize how proteins involved in the transcriptional corepressor complex, various post-translational modifications, and metabolites act as regulatory factors for LSD1 activity.

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The abnormal activation of Cullin RING E3 Ligases (CRLs) is closely associated with the occurrence and development of various cancers. Targeting the neddylation pathway represents an effective approach for cancer treatment. In this work, we reported that WS-299, structurally featuring a coumarin moiety attached to the triazolopyrimidine, exhibited excellent anti-proliferative activity in MGC-803 and HGC-27 cells. WS-299 exerted potent anticancer effects by inhibiting clone formation, EdU incorporation and inducing cell cycle arrest. WS-299 inhibited CUL3/5 neddylation and caused an obvious accumulation of Nrf2 and NOXA, substrates of CRL3 and CRL5, respectively. Biochemical studies showed that WS-299 inhibited CUL3 neddylation by inhibiting RBX1-UBE2M interaction. The anti-proliferative effect of WS-299 was mainly induced by NOXA-mediated apoptosis. Of note, Nrf2 attenuated WS-299-induced reactive oxygen species (ROS) levels. Furthermore, Nrf2 accumulation also had an antagonistic effect on NOXA-induced apoptosis. Therefore, WS-299 and siNrf2 synergistically increased ROS levels, apoptotic cells and suppressed tumor growth in vivo. Taken together, our research clarified the anti-cancer mechanisms of WS-299 through targeting the RBX1-UBE2M protein-protein interaction and inhibiting the neddylation modification of CUL3 and CUL5. More importantly, our studies also demonstrated that combination of WS-299 with shNrf2 could be an effective strategy for treating gastric cancers.

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p62 is an important multifunctional adaptor protein participating in autophagy and many other activities. Many studies have revealed that p62 is highly expressed in multiple cancers and decreasing its level can effectively lower the proliferation ability of cancer cells. Moreover, much research has highlighted the significant role of the regulation of cancer cell metabolism in helping to treat tumors. Recent reports demonstrate that p62 could regulate cancer cell metabolism through various mechanisms. However, the relationship between p62 and cancer cell metabolism as well as the related mechanisms has not been fully elucidated. In this review, we describe glucose, glutamine, and fatty acid metabolism in tumor cells and some signaling pathways that can regulate cancer metabolism and are mediated by p62.

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The framing effect refers to the phenomenon that different descriptions of the same option lead to a shift in the choice of the decision maker. Several studies have found that emotional contexts irrelevant to a decision in progress still influence the framing effect on decision making. However, little is known about the potential role of emotional contexts in the framing effect on outcome evaluation under uncertainty and the related neural mechanisms. The present study measured event-related potentials (ERPs) to capture the time series of brain activities during the processing of gain- and loss-framed choices and outcomes primed with neutral and negative emotional contexts. The results revealed that in the neutral emotional context, the P300 amplitudes following both positive and negative feedback were greater in the gain-framed condition than those in the loss-framed condition, demonstrating a framing effect, whereas in the negative emotional context, this effect was unstable and observed only following negative feedback. In contrast, regardless of whether the feedback was positive or negative, the framing effect on the feedback-related negativity (FRN) amplitudes was insensitive to neutral and negative emotional contexts. Furthermore, the time-frequency analysis showed that the framing effect on the theta power related to the FRN was also insensitive to neutral and negative emotional contexts. Our findings suggest that brain responses to framing effects on outcome evaluation in a later cognitive appraisal stage of decision making under uncertainty may depend on the emotional context, as the effects were observed only following negative feedback in the negative emotional context.

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Introduction: Advice-giving is a double-edged sword in social interaction, which could bring benefits or considerable losses for the advisee. However, whether the social relationship affects the time course of advisor's brain response to outcome evaluation after the advice-giving remains unclear. Methods: In the present study, we used event-related potentials (ERPs) to investigate the modulation of social relationships on advisor's outcome feedback processing after the advice-giving and related neural activities. Results: The results showed larger feedback-related negativity (FRN) to a loss than to a gain both when the friends accepted and rejected the advice, whereas this effect only existed when the strangers rejected the advice, but not when they accepted it. In contrast, the P3 results demonstrated the enhanced neural sensitivity when the strangers accepted the advice than rejected it despite leading to a loss, while a larger P3 amplitude was found when the friends accepted the advice than rejected it and brought a gain. The theta oscillation results in the friend group revealed stronger theta power to loss when the advisee accepted the advice than rejected it. However, this effect was absent in the stranger group. Discussion: These results suggested that outcome evaluation in advice-giving was not only influenced by feedback valence and social reward, but also modulated by social relationships. Our findings contributed to the understanding of the neural mechanisms of advice-giving outcome evaluation in a social context.