MORC2 regulates C/EBPα-mediated cell differentiation via sumoylation

Abstract

The expression and activity of CCAAT/enhancer-binding protein α (C/EBPα) are involved in sumoylation modification, which is critical to divert normal cells from differentiation to proliferation. However, the role and underlying mechanism of C/EBPα in cancer is poorly understood. Human MORC2 (microrchidia family CW-type zinc-finger 2), is a member of the MORC proteins family containing a CW-type zinc-finger domain. Here, we found that MORC2 interacted with TE-III domain of C/EBPα, and the overexpression of MORC2 promoted wild-type C/EBPα sumoylation and its subsequent degradation, which didn’t significantly observe in mutant C/EBPα-K161R. Furthermore, the overexpression of MORC2 inhibited C/EBPα-mediated C2C12 cell differentiation to maintain cell cycle progression. Moreover, the striking correlation between the decreased C/EBPα expression and the increased MORC2 expression was also observed in the poor differentiation status of gastric cancer tissues. Most notably, the high expression of MORC2 is correlated with an aggressive phenotype of clinical gastric cancer and shorter overall survival of patients. Taken together, our findings demonstrated that MORC2 expression regulated C/EBPα-mediated the axis of differentiation/proliferation via sumoylation modification, and affected its protein stability, causing cell proliferation and tumorigenesis.

Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor

“…Mutations in genes involved in neuronal/muscular differentiation, and differentiation defects were linked to dHMNs. For example, IGHMBP2 leads to differentiation defects in motoneurons and is mutated in Charcot–Marie–Tooth (CMT) 2S; 73 MORC2 is a chromatin-remodeling protein regulating differentiation and mutated in CMT; 74 NDRG1 promotes differentiation and is mutated in CMT4D; 75 Sbf1/Sbf2 are epigenetic regulators of cell differentiation and are mutated in CMT 76 , 77 .…”

CDK2 destabilizes tumor suppressor C/EBPα expression through ubiquitin‐mediated proteasome degradation in acute myeloid leukemia

“…[8][9][10] C/EBPα posttranslational modifications including ubiquitination, which is catalyzed by E3 ubiquitin ligases have been shown to regulate both function and expression of C/EBPα. 5,[11][12][13][14][15][16] In a previous study, we also reported reduced C/EBPα steady-state levels through enhanced ubiquitin-mediated proteasome degradation by E6AP. 17 However, mechanisms regulating C/EBPα protein stability in diseases are poorly known.…”

“…Therefore, dysregulated expression and functional inhibition of C/EBPα is associated with block in myeloid differentiation and leukemogenesis . C/EBPα posttranslational modifications including ubiquitination, which is catalyzed by E3 ubiquitin ligases have been shown to regulate both function and expression of C/EBPα . In a previous study, we also reported reduced C/EBPα steady‐state levels through enhanced ubiquitin‐mediated proteasome degradation by E6AP .…”

SUMOylation of TUFT1 is essential for gastric cancer progression through AKT/mTOR signaling pathway activation

“…Several studies have shown that expression of the core SUMOylation machinery (E1 activating enzyme, E2 conjugating enzyme, several E3 ligases, and SUMO1/sentrin specific peptidases) is enhanced in GC, 7–10 suggesting that SUMOylation is closely related to the survival and malignant behavior of GC cells. However, only a few transcription factors and receptors such as forkhead box protein C2 (FOXC2), N‐myc downstream‐regulated gene 2 (NDRG2), Sp1, CCAAT/enhancer‐binding protein alpha (C/EBPα), insulin‐like growth factor 1 receptor (IGF‐1R), and death domain‐associated protein 6 (DAXX) have been reported to be SUMOylated in GC 10–15 . Uncovering the roles of more SUMOylated proteins in GC will provide a promising perspective for investigating the molecular mechanism of tumorigenesis and progression, finding novel biomarkers with higher sensitivity, and contributing to the early diagnosis and targeted therapies of GC.…”

“…However, only a few transcription factors and receptors such as forkhead box protein C2 (FOXC2), N-myc downstreamregulated gene 2 (NDRG2), Sp1, CCAAT/enhancer-binding protein alpha (C/EBPα), insulin-like growth factor 1 receptor (IGF-1R), and death domain-associated protein 6 (DAXX) have been reported to be SUMOylated in GC. [10][11][12][13][14][15] Uncovering the roles of more SUMOylated proteins in GC will provide a promising perspective for investigating the molecular mechanism of tumorigenesis and progression, finding novel biomarkers with higher sensitivity, and contributing to the early diagnosis and targeted therapies of GC. Tuftelin (TUFT1) was initially characterized as a protein involved in tooth enamel mineralization in vertebrates and subsequently found in nonmineralized tissues such as lung, stomach, and liver.…”