MED15 is upregulated by HIF-2α and promotes proliferation and metastasis in clear cell renal cell carcinoma via activation of SREBP-dependent fatty acid synthesis

作者全名：Hua, Xiaoliang; Ge, Shengdong; Zhang, Li; Jiang, Qing; Chen, Juan; Xiao, Haibing; Liang, Chaozhao

作者地址：[Hua, Xiaoliang; Jiang, Qing; Chen, Juan] Chongqing Med Univ, Affiliated Hosp 2, Dept Urol, Chongqing, Peoples R China; [Hua, Xiaoliang; Ge, Shengdong; Zhang, Li; Xiao, Haibing; Liang, Chaozhao] Anhui Med Univ, Affiliated Hosp 1, Dept Urol, Hefei, Peoples R China; [Chen, Juan] Chongqing Med Univ, Coll Lab Med, Minist Educ, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China

通信作者：Chen, J (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Urol, Chongqing, Peoples R China.; Xiao, HB; Liang, CZ (通讯作者)，Anhui Med Univ, Affiliated Hosp 1, Dept Urol, Hefei, Peoples R China.; Chen, J (通讯作者)，Chongqing Med Univ, Coll Lab Med, Minist Educ, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China.

来源：CELL DEATH DISCOVERY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001206114800005

JCR分区：Q1

影响因子：6.1

年份：2024

卷号：10

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要：Emerging evidence has highlighted that dysregulation of lipid metabolism in clear cell renal cell carcinoma (ccRCC) is associated with tumor development and progression. HIF-2 alpha plays an oncogenic role in ccRCC and is involved in abnormal lipid accumulation. However, the underlying mechanisms between these two phenomena remain unknown. Here, MED15 was demonstrated to be a dominant factor for HIF-2 alpha-dependent lipid accumulation and tumor progression. HIF-2 alpha promoted MED15 transcriptional activation by directly binding the MED15 promoter region, and MED15 overexpression significantly alleviated the lipid deposition inhibition and malignant tumor behavior phenotypes induced by HIF-2 alpha knockdown. MED15 was upregulated in ccRCC and predicted poor prognosis. MED15 promoted lipid deposition and tumor progression in ccRCC. Mechanistic investigations demonstrated that MED15 acts as SREBP coactivator directly interacting with SREBPs to promote SREBP-dependent lipid biosynthesis enzyme expression, and promotes SREBP1 and SREBP2 activation through the PLK1/AKT axis. Overall, we describe a molecular regulatory network that links MED15 to lipid metabolism induced by the SREBP pathway and the classic HIF-2 alpha pathway in ccRCC. Efforts to target MED15 or inhibit MED15 binding to SREBPs as a novel therapeutic strategy for ccRCC may be warranted.

基金机构：National Natural Science Foundation of China (National Science Foundation of China) [81870519, 82203591]; National Natural Science Foundation of China [cstc2021jcyj-msxm0317]; Natural Science Foundation of Chongqing Science and Technology [KJQN202100418, 81902584]; Science and Technology Research Plan Project of Chongqing Education Commission [2022APKLGUD05]; Anhui Province Key Laboratory of Genitourinary Diseases Foundation

基金资助正文：This study was funded by National Natural Science Foundation of China (81870519) to CZL, National Natural Science Foundation of China (82203591), Natural Science Foundation of Chongqing Science and Technology (cstc2021jcyj-msxm0317), Science and Technology Research Plan Project of Chongqing Education Commission (KJQN202100418) to JC, National Natural Science Foundation of China (81902584) to HBX, and Anhui Province Key Laboratory of Genitourinary Diseases Foundation (2022APKLGUD05) to XLH.