Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
Shanghai University of Medicine & Health Sciences, China.
Mol Oncol. 2018 Sep;12(9):1480-1497. doi: 10.1002/1878-0261.12357. Epub 2018 Aug 7.
Although identified as a growth factor, the mechanism by which hepatoma-derived growth factor (HDGF) promotes cancer development remains unclear. We found that nuclear but not cytoplasmic HDGF is closely associated with prognosis of hepatocellular carcinoma (HCC). RNA-sequencing analysis further demonstrated that the nuclear role of HDGF involved regulation of transcription of lipid metabolism genes. HDGF-induced expression of lipogenic genes was mainly associated with activation of sterol regulatory element binding protein (SREBP) transcription factor. Coexpression of SREBP-1 and nuclear HDGF predicts poor prognosis for HCC. In addition, by changing the first amino acid of the PWWP domain from proline to alanine, the type of PWWP domain changed from P- to A-type, resulting in inability to induce SREBP-1-mediated gene transcription. The type of PWWP domain affects the recruitment of the C-terminal binding protein-1 transcriptional repressor on the promoter of the lipogenic gene. Our data indicate that HDGF acts as a coactivator of SREBP1-mediated transcription of lipogenic genes. The PWWP domain is crucial for HDGF to promote lipogenesis. Moreover, transcriptional regulation of nuclear HDGF plays important roles in the development of HCC.
虽然已被鉴定为生长因子，但肝癌衍生生长因子（HDGF）促进癌症发展的机制仍不清楚。我们发现核内而非细胞质中的 HDGF 与肝细胞癌（HCC）的预后密切相关。RNA 测序分析进一步表明，HDGF 的核作用涉及脂质代谢基因转录的调节。HDGF 诱导的生脂基因表达主要与固醇调节元件结合蛋白（SREBP）转录因子的激活有关。SREBP-1 和核内 HDGF 的共表达预测 HCC 的预后不良。此外，通过将 PWWP 结构域的第一个氨基酸从脯氨酸变为丙氨酸，PWWP 结构域的类型从 P 型变为 A 型，导致无法诱导 SREBP-1 介导的基因转录。PWWP 结构域的类型影响 C 端结合蛋白-1 转录抑制剂在生脂基因启动子上的募集。我们的数据表明，HDGF 作为 SREBP1 介导的生脂基因转录的共激活因子发挥作用。PWWP 结构域对于 HDGF 促进生脂作用至关重要。此外，核内 HDGF 的转录调控在 HCC 的发展中起重要作用。
