Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
The Institute of Cell Metabolism, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
Cancer Sci. 2020 Apr;111(4):1266-1278. doi: 10.1111/cas.14348. Epub 2020 Mar 16.
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.
琥珀酸脱氢酶（SDH）缺陷与胃肠道间质瘤（GIST）的发生有关，但潜在的分子机制仍需进一步研究。在这里，我们表明 SDHB 功能丧失引起的琥珀酸积累增加了 GIST 细胞中锌指蛋白 148（ZNF148，也称为 ZBP-89）的表达。同时，发现 ZNF148 在丝氨酸 306 处被 ERK 磷酸化，这种磷酸化导致 ZNF148 与 Forkhead box M1（FOXM1）结合。通过启动子的复合物形成，ZNF148 促进组蛋白 H3 乙酰化和 FOXM1 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 缺陷与 ZNF148 水平升高有关，并且 ZNF148-S306 磷酸化水平与 GIST 患者的预后不良呈正相关。这些发现说明了与 GIST 细胞侵袭相关的 FOXM1 调节基因转录的一个未被识别的分子机制，突出了 SDHB 缺陷对 GIST 侵袭性的生理影响。
