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

doi:10.1016/j.molcel.2022.06.003

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

Mol Cell. 2022 Aug 18;82(16):3030-3044.e8. doi: 10.1016/j.molcel.2022.06.003. Epub 2022 Jun 27.

Authors

Jin Zhou¹, Jeremy M Simon², Chengheng Liao¹, Cheng Zhang¹, Lianxin Hu¹, Giada Zurlo¹, Xijuan Liu³, Cheng Fan³, Austin Hepperla², Liwei Jia¹, Vanina Toffessi Tcheuyap⁴, Hua Zhong⁵, Roy Elias⁴, Jin Ye⁶, W Mike Henne⁷, Payal Kapur⁸, Deepak Nijhawan⁹, James Brugarolas⁴, Qing Zhang¹⁰

Affiliations

¹ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² 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.
³ Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁴ 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.
⁵ 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.
⁶ Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁸ 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.
⁹ 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.
¹⁰ 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: qing.zhang@utsouthwestern.edu.

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.

Keywords: 2-OG-dependent dioxygenases; DGAT1; JMJD6; ccRCC; lipid droplet.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Carcinogenesis / genetics
Carcinoma, Renal Cell* / genetics
Diacylglycerol O-Acyltransferase* / genetics
Diacylglycerol O-Acyltransferase* / metabolism
Epigenesis, Genetic
Humans
Jumonji Domain-Containing Histone Demethylases* / genetics
Jumonji Domain-Containing Histone Demethylases* / metabolism
Kidney Neoplasms* / genetics
Lipid Droplets / metabolism

Substances

JMJD6 protein, human
Jumonji Domain-Containing Histone Demethylases
DGAT1 protein, human
Diacylglycerol O-Acyltransferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding