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.
Molecular cell. 2022 Jun 15 [Epub ahead of print]
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
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., Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA., Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: .