Upregulation of ZNF148 in SDHB-deficient gastrointestinal stromal tumor potentiates Forkhead box M1-mediated transcription and promotes tumor cell invasion
Upregulation of ZNF148 in SDHB-deficient gastrointestinal stromal tumor potentiates Forkhead box M1-mediated transcription and promotes tumor cell invasion
复制标题
SDHB 缺陷的胃肠道间质瘤中 ZNF148 的上调增强了 Forkhead box M1 介导的转录并促进肿瘤细胞侵袭
DOI：
10.1111/cas.14348
复制
发表时间：
2020-04-01
期刊：
影响因子：
5.7
通讯作者：
Shen, Xian
中科院分区：
文献类型：
--
作者：
Gao, Xiaodong;Ma, Chunmin;Shen, Xian
琥珀酸脱氢酶（SDH）缺乏与胃肠道间质瘤（GIST）的发生有关，但其分子机制仍有待进一步研究。在这里，我们表明，琥珀酸积累引起的SDHB功能丧失增加锌指蛋白148（ZNF 148，也称为ZBP-89）在GIST细胞的表达。同时，ZNF 148被ERK在Ser 306处磷酸化，这种磷酸化导致ZNF 148与Forkhead box M1（FOXM 1）结合。通过在启动子处形成复合物，ZNF 148促进组蛋白H3乙酰化和FOXM 1介导的Snail转录，最终促进细胞侵袭和肿瘤生长。临床分析表明，SDHB缺乏与ZNF 148水平升高相关，ZNF 148-S306磷酸化水平与GIST患者预后不良呈正相关。这些发现说明了一个未知的分子机制，FOXM 1调控的基因转录与GIST细胞侵袭相关，这突出了SDHB缺乏对GIST侵袭性的生理影响。
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.