Open AccessUpregulation of ZNF148 in SDHB‐deficient gastrointestinal stromal tumor potentiates Forkhead box M1‐mediated transcription and promotes tumor cell invasion
Author(s) -
Gao Xiaodong,
Ma Chunmin,
Sun Xiangwei,
Zhao Qin,
Fang Yong,
Jiang Yuhui,
Shen Kuntang,
Shen Xian
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14348
Subject(s) - sdhb , gist , cancer research , biology , stromal cell , foxm1 , stromal tumor , carcinogenesis , downregulation and upregulation , transcription factor , mapk/erk pathway , phosphorylation , cell cycle , microbiology and biotechnology , cell , cancer , gene , mutation , biochemistry , germline mutation , genetics
Succinate dehydrogenase (SDH) deficiency is associated with gastrointestinal stromal tumor (GIST) oncogenesis, but the underlying molecular mechanism remains to be further investigated. Here, we show that succinate accumulation induced by SDHB loss of function increased the expression of zinc finger protein 148 (ZNF148, also named ZBP‐89) in GIST cells. Meanwhile, ZNF148 is found to be phosphorylated by ERK at Ser306, and this phosphorylation results in ZNF148 binding to Forkhead box M1 (FOXM1). Through the complex formation at the promoter, ZNF148 facilitates Histone H3 acetylation and FOXM1‐mediated Snail transcription, which eventually promotes cell invasion and tumor growth. The clinical analysis indicates that SDHB deficiency is associated with elevated ZNF148 levels, and ZNF148‐S306 phosphorylation level displays a positive correlation with poor prognosis in GIST patients. These findings illustrate an unidentified molecular mechanism underlying FOXM1‐regulated gene transcription related to GIST cell invasion, which highlights the physiological effects of SDHB deficiency on the invasiveness of GIST.