The UbL-UBA Ubiquilin4 protein functions as a tumor suppressor in gastric cancer by p53-dependent and p53-independent regulation of p21

被引:44
作者
Huang, Shengkai [1 ,2 ,3 ,4 ]
Li, Yan [1 ,2 ,3 ,5 ]
Yuan, Xinghua [6 ]
Zhao, Mei [1 ,2 ,3 ,5 ]
Wang, Jia [7 ]
Li, You [8 ,9 ,10 ]
Li, Yuan [11 ]
Lin, Hong [1 ,2 ,3 ,5 ]
Zhang, Qiao [1 ,2 ,3 ,5 ]
Wang, Wenjie [1 ,2 ,3 ,5 ]
Li, Dongdong [1 ,2 ,3 ,5 ]
Dong, Xin [2 ,4 ]
Li, Lanfen [12 ]
Liu, Min [8 ]
Huang, Weiyan [1 ,2 ,3 ,13 ]
Huang, Changzhi [1 ,2 ,3 ,5 ]
机构
[1] Chinese Acad Med Sci, State Key Lab Mol Oncol, Natl Canc Ctr, Canc Hosp, Beijing 100021, Peoples R China
[2] Peking Union Med Coll, Beijing 100021, Peoples R China
[3] Chinese Acad Med Sci, Dept Etiol & Carcinogenesis, Natl Canc Ctr, Canc Hosp, Beijing 100021, Peoples R China
[4] Chinese Acad Med Sci, Dept Clin Lab, Natl Canc Ctr, Canc Hosp, Beijing 100021, Peoples R China
[5] Beijing Key Lab Carcinogenesis & Canc Prevent, Beijing 100021, Peoples R China
[6] Chinese Acad Med Sci, Dept Abdomen Surg, Natl Canc Ctr, Canc Hosp, Beijing 100021, Peoples R China
[7] Meitan Gen Hosp, Dept Clin Lab, Beijing 100021, Peoples R China
[8] Xiamen Univ, State Key Lab Cellular Stress Biol, Sch Life Sci, Fuzhou 361005, Fujian, Peoples R China
[9] Univ Canterbury, Biomol Interact Ctr, Christchurch 8140, New Zealand
[10] Univ Canterbury, Dept Chem, Christchurch 8140, New Zealand
[11] China Med Univ, Dept Dev Biol, Shenyang 110122, Liaoning, Peoples R China
[12] Peking Univ, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China
[13] Ohio State Univ, Dept Vet Biosci, Columbus, OH 43210 USA
基金
中国国家自然科学基金;
关键词
CELL-CYCLE; EXPRESSION; P53; P21(WAF1/CIP1); SENESCENCE; ARREST; UBIQUITINATION; IDENTIFICATION; LOCALIZATION; MODULATION;
D O I
10.1038/s41418-018-0141-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ubiquilin4 (Ubqln4), a member of the UbL-UBA protein family, serves as an adaptor in the degradation of specific substrates via the proteasomal pathway. However, the biological function of Ubqln4 remains largely unknown, especially in cancer. Here, we reported that Ubqln4 was downregulated in gastric cancer tissues and functioned as a tumor suppressor by inhibiting gastric cancer cell proliferation in vivo and in vitro. Overexpression of Ubqln4-induced cellular senescence and G1-S cell cycle arrest in gastric cancer cells and activated the p53/p21 axis. Moreover, Ubqln4 regulated p21 through both p53-dependent and p53-independent manners. Ubqln4 interacted with RNF114, an E3 ubiquitin ligase of p21, and negatively regulated its expression level, which in turn stabilized p21 by attenuating proteasomal degradation of p21. These effects of Ubqln4 were partly abrogated in gastric cancer cells upon silencing of p21. Our findings not only establish the anti-tumor potential of Ubqln4 in gastric cancer but also reveal a role for Ubqln4 in regulation of the cell cycle and cellular senescence via stabilizing p21.
引用
收藏
页码:516 / 530
页数:15
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