Premium
Heat‐Shock protein A12A is a novel PCNA‐binding protein and promotes hepatocellular carcinoma growth
Author(s) -
Cheng Hao,
Cao Xiaofei,
Min Xinxu,
Zhang Xiaojin,
Kong Qiuyue,
Mao Qian,
Li Rongrong,
Xue Bin,
Fang Lei,
Liu Li,
Ding Zhengnian
Publication year - 2020
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15276
Subject(s) - proliferating cell nuclear antigen , gene knockdown , cancer research , carcinogenesis , cell growth , angiogenesis , hepatocellular carcinoma , nuclear protein , biology , immunoprecipitation , heat shock protein , microbiology and biotechnology , chemistry , cancer , cell culture , apoptosis , transcription factor , biochemistry , gene , genetics
Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death. Proliferating cell nuclear antigen (PCNA) plays a pivotal role in cancer development and progression. However, the long‐term dismal prognosis of HCC mandates more investigation to identify novel regulators in HCC pathogenesis. Heat‐shock protein A12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that HCC cells showed increased HSPA12A expression, and overexpression of HSPA12A promoted HCC growth and angiogenesis in mice. Gain‐ and loss‐of‐functional studies demonstrated that the proliferation of HCC HepG2 cells, as well as β‐catenin expression and nuclear translocation, was promoted by HSPA12A overexpression, but in turn suppressed by HSPA12A knockdown. HSPA12A did not impact PCNA expression; however, mass spectrometry and co‐immunoprecipitation immunoblotting analysis revealed that HSPA12A directly binds to PCNA and promotes its trimerization, which is an essential functional conformation of PCNA for carcinogenesis. Importantly, PCNA inhibition by PCNA‐I1 reversed the HSPA12A‐mediated HepG2 cell differentiation. These findings indicate that HSPA12A is a novel regulator of HCC cell proliferation and tumor growth through binding to PCNA for its trimerization. HSPA12A inhibition might represent a viable strategy for the management of HCC in humans.