MORC2 regulates C/EBP\u03b1-mediated cell differentiation via sumoylation

Jia Liu,Zhifeng Miao,Qing Zhang,Liu Cao,Feng Li,Guiling Wang,Banlai Ruan,Buxuan Xu,Jessie Yanxiang Guo,Jianyu Zheng,Wei Chen,Peijia Jiang

doi:10.1038/s41418-018-0259-4

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.

Highlights

The tumorigenesis is a multistep process with numerous changes in cell proliferation, differentiation, and/or survival [1]
A series of purified GST-fused CCAAT/enhancer-binding protein α (C/EBPα) proteins corresponding to the truncation and deletion constructs were performed by GST pull-down assays, and indicated that in vitro-translated MORC2 bound to the full length GST-C/EBPα, GST-C1, Fig. 1 MORC2 interacts with TE-III domain of C/EBPα. a MORC2 directly binds C/EBPα in vitro
GST-C2, GST-C4 but not GST-C3, GST-C5 or GST alone, showing that in vitro-translated MORC2 could bind to the GST-C4 (103–212) of C/EBPα (Fig. 1e), which is within TE-III domain [4]

Summary

1234567890();,: 1234567890();,: Introduction

The tumorigenesis is a multistep process with numerous changes in cell proliferation, differentiation, and/or survival [1]. Modification of C/EBPα by SUMO-1 at lysine reside 161 lies within the TE-III domain, which enables binding to specific proteins to affect its level of the sumoylation [8,9,10]. Our research indicated that MORC2 promoted gastric cancer cell proliferation and tumorigenesis [20, 21]. The increased MORC2 expression negatively correlates with the decreased C/EBPα, which was shown in the differentiation status of gastric cancer samples. These results open a new line of study on the underlying mechanism of down-regulated C/EBPα expression in cancer, and identify that MORC2 plays an important role in control C/EBPα-mediated the axis of differentiation/proliferation, which is involved in tumorigenesis

Results

Discussion

Methods

Compliance with ethical standards