Open AccessE3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non–small cell lung cancer
Author(s) -
Ké Li,
Xufen Zheng,
Hua Tang,
YuanSheng Zang,
Chunling Zeng,
Xiaoxiao Liu,
Yanying Shen,
Yu Pang,
Simin Wang,
Feifei Xie,
Xiao-Jing Lu,
Yang Luo,
Zhang Li,
Wenbo Bi,
Jia Xing,
Tao Huang,
Rongqiang Wei,
Kenan Huang,
Zihao Chen,
Qingchen Zhu,
Yi He,
Miaoying Zhang,
Zhizhan Gu,
Yichuan Xiao,
Xiaoyang Zhang,
Jonathan A. Fletcher,
Yuexiang Wang
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20210151
Subject(s) - ubiquitin ligase , cancer research , carcinogenesis , biology , cell growth , tumor suppressor gene , microbiology and biotechnology , gene knockdown , ubiquitin , cancer , cell culture , biochemistry , genetics , gene
Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non–small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations. Low MKRN3 expression levels correlate with poor patient survival. Reconstitution of MKRN3 in MKRN3-inactivated NSCLC cells directly abrogates in vitro and in vivo tumor growth and proliferation. MKRN3 knockout mice are susceptible to urethane-induced lung cancer, and lung cell–specific knockout of endogenous MKRN3 accelerates NSCLC tumorigenesis in vivo. A mass spectrometry–based proteomics screen identified PABPC1 as a major substrate for MKRN3. The tumor suppressor function of MKRN3 is dependent on its E3 ligase activity, and MKRN3 missense mutations identified in patients substantially compromise MKRN3-mediated PABPC1 ubiquitination. Furthermore, MKRN3 modulates cell proliferation through PABPC1 nonproteolytic ubiquitination and subsequently, PABPC1-mediated global protein synthesis. Our integrated approaches demonstrate that the CPP-associated gene MKRN3 is a tumor suppressor.