An oncogenic JMJD6-DGAT1 axis tunes the epigenetic regulation of lipid droplet formation in clear cell renal cell carcinoma

Jin Zhou, Jeremy M. Simon, Chengheng Liao, Cheng Zhang, Lianxin Hu, Giada Zurlo, Xijuan Liu, Cheng Fan, Austin Hepperla, Liwei Jia, Vanina Toffessi Tcheuyap, Hua Zhong, Roy Elias, Jin Ye, W. Mike Henne, Payal Kapur, Deepak Nijhawan, James Brugarolas, Qing Zhang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3030-3044.e8
JournalMolecular cell
Volume82
Issue number16
DOIs
StatePublished - Aug 18 2022

Keywords

  • 2-OG-dependent dioxygenases
  • ccRCC
  • DGAT1
  • JMJD6
  • lipid droplet

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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