2. Academic Validation
  3. CMTM6 inhibits tumor growth and reverses chemoresistance by preventing ubiquitination of p21 in hepatocellular carcinoma

CMTM6 inhibits tumor growth and reverses chemoresistance by preventing ubiquitination of p21 in hepatocellular carcinoma

  • Cell Death Dis. 2022 Mar 19;13(3):251. doi: 10.1038/s41419-022-04676-1.
Yue Huang # 1 2,  Yingqin Zhu # 3,  Jieying Yang # 1 2,  Qiuzhong Pan 1 2,  Jingjing Zhao 1 2,  Mengjia Song 1 2,  Chaopin Yang 1 2,  Yulong Han 1 2,  Yan Tang 1 2,  Qijing Wang 1 2,  Jia He 1 2,  Yongqiang Li 1 2,  Junyi He 1 2,  Hao Chen 1 2,  Desheng Weng 1 2,  Tong Xiang 4 5,  Jian Chuan Xia 6 7
Affiliations

Affiliations

  • 1 Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
  • 2 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 Department of Pancreato-Biliary Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 4 Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China. xiangtong@sysucc.org.cn.
  • 5 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China. xiangtong@sysucc.org.cn.
  • 6 Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China. xiajch@mail.sysu.edu.cn.
  • 7 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China. xiajch@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 35304440 DOI: 10.1038/s41419-022-04676-1
Abstract

Hepatocellular carcinoma is one of the most common malignancies and has a poor prognosis. The ubiquitin-proteasome pathway is required for the degradation of most short-lived proteins. CMTM6 has been implicated in the progression of various tumors, but its biological function and the underlying molecular mechanisms in HCC are still unknown. In this study, we found that the expression of CMTM6 was significantly reduced in HCC and predicted better prognosis of HCC patients. Through in vitro and in vivo experiments, CMTM6 was shown to inhibit the proliferation of HCC cells by blocking the G1/S phase transition. Mechanistically, CMTM6 interacted with p21 and prevented its ubiquitination mediated by SCFSKP2, CRL4CDT2 and APC/CCDC20 in a cell-cycle-independent manner. As a result, CMTM6 stabilized p21 protein, leading to the inactivation of pRB/E2F pathway. Additionally, CMTM6 sensitized HCC cells to doxorubicin and cisplatin, positively correlated with better clinical outcomes of the transarterial chemoembolization (TACE) treatment for postoperative recurrence. Taken together, our study reports a novel mechanism by which p21 can be stabilized by CMTM6 and pinpoints a crucial role of the CMTM6-p21 axis in suppressing the progression of HCC and sensitizing patients with postoperative recurrence to TACE treatment.

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