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.