致癌 JMJD6-DGAT1 轴调节透明细胞肾细胞癌中脂滴形成的表观遗传调控。
An oncogenic JMJD6-DGAT1 axis tunes the epigenetic regulation of lipid droplet formation in clear cell renal cell carcinoma.
机构信息
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Department of Genetics, Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA.
出版信息
Mol Cell. 2022 Aug 18;82(16):3030-3044.e8. doi: 10.1016/j.molcel.2022.06.003. Epub 2022 Jun 27.
Characterized by intracellular lipid droplet accumulation, clear cell renal cell carcinoma (ccRCC) is resistant to cytotoxic chemotherapy and is a lethal disease. Through an unbiased siRNA screen of 2-oxoglutarate (2-OG)-dependent enzymes, which play a critical role in tumorigenesis, we identified Jumonji domain-containing 6 (JMJD6) as an essential gene for ccRCC tumor development. The downregulation of JMJD6 abolished ccRCC colony formation in vitro and inhibited orthotopic tumor growth in vivo. Integrated ChIP-seq and RNA-seq analyses uncovered diacylglycerol O-acyltransferase 1 (DGAT1) as a critical JMJD6 effector. Mechanistically, JMJD6 interacted with RBM39 and co-occupied DGAT1 gene promoter with H3K4me3 to induce DGAT1 expression. JMJD6 silencing reduced DGAT1, leading to decreased lipid droplet formation and tumorigenesis. The pharmacological inhibition (or depletion) of DGAT1 inhibited lipid droplet formation in vitro and ccRCC tumorigenesis in vivo. Thus, the JMJD6-DGAT1 axis represents a potential new therapeutic target for ccRCC.
特征为细胞内脂滴积累，透明细胞肾细胞癌（ccRCC）对细胞毒性化疗具有抗性，是一种致命的疾病。通过对 2-氧戊二酸（2-OG）依赖性酶的无偏 siRNA 筛选，这些酶在肿瘤发生中起着关键作用，我们鉴定出包含 Jumonji 结构域的 6 号（JMJD6）是 ccRCC 肿瘤发展的必需基因。JMJD6 的下调消除了体外 ccRCC 集落形成，并抑制了体内原位肿瘤生长。整合的 ChIP-seq 和 RNA-seq 分析揭示了二酰基甘油 O-酰基转移酶 1（DGAT1）是关键的 JMJD6 效应物。在机制上，JMJD6 与 RBM39 相互作用，并与 H3K4me3 共同占据 DGAT1 基因启动子，从而诱导 DGAT1 表达。JMJD6 沉默减少了 DGAT1，导致脂滴形成减少和肿瘤发生。DGAT1 的药理学抑制（或耗竭）抑制了体外脂滴形成和体内 ccRCC 肿瘤发生。因此，JMJD6-DGAT1 轴代表了 ccRCC 的一个潜在新的治疗靶点。
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