@article{78024e25c8ed4d83864d2c1cbe9c9df8,
title = "An oncogenic JMJD6-DGAT1 axis tunes the epigenetic regulation of lipid droplet formation in clear cell renal cell carcinoma",
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",
author = "Jin Zhou and Simon, {Jeremy M.} and Chengheng Liao and Cheng Zhang and Lianxin Hu and Giada Zurlo and Xijuan Liu and Cheng Fan and Austin Hepperla and Liwei Jia and Tcheuyap, {Vanina Toffessi} and Hua Zhong and Roy Elias and Jin Ye and Henne, {W. Mike} and Payal Kapur and Deepak Nijhawan and James Brugarolas and Qing Zhang",
note = "Funding Information: This work was partially supported by the Cancer Prevention and Research Institute of Texas ( CPRIT ) (Q.Z., CPRIT, RR190058 ), the Department of Defense Kidney Cancer Research Program Idea Development Award ( W81XWH1910813 ), and the National Cancer Institute (Q.Z., R01CA211732 , J.B., P50CA196516 ). D.N. is supported by R37CA226771 from the NCI, a Welch Foundation Award (I-1879), and a UT Presidential Scholar Award. We thank Dr. Jian Xu and the Sequencing Facility of Children{\textquoteright}s Medical Center Research Institute (CRI) at UT Southwestern for their help. We thank the UTSW Tissue Management Shared Resource Center at the Simmons Comprehensive Cancer Center, which is supported in part by the National Cancer Institute under award number P30 CA142543 . We acknowledge the assistance of the Preclinical Radiation Core Facility, which is supported by CPRIT ( RP180770 ). We thank Dr. Ralph DeBerardinis{\textquoteright}s guidance, Dr. Lei Bao and Prof. Weibo Luo for the ChIP technical support and MLL-C antibody sharing, Dr. Xiang Cheng and Prof. Deliang Guo for providing the DGAT1 shRNA/sgRNA plasmids, Dr. Jaeil Han and Prof. Joshua Mendell for providing ZSWIM8 plasmid, and Dr. Sabine Lang and Prof. Qin Yan for providing the MLLs antibodies. We also want to thank the kidney cancer patients for donating their tissues for this study. Funding Information: This work was partially supported by the Cancer Prevention and Research Institute of Texas (CPRIT) (Q.Z. CPRIT, RR190058), the Department of Defense Kidney Cancer Research Program Idea Development Award (W81XWH1910813), and the National Cancer Institute (Q.Z. R01CA211732, J.B. P50CA196516). D.N. is supported by R37CA226771 from the NCI, a Welch Foundation Award (I-1879), and a UT Presidential Scholar Award. We thank Dr. Jian Xu and the Sequencing Facility of Children's Medical Center Research Institute (CRI) at UT Southwestern for their help. We thank the UTSW Tissue Management Shared Resource Center at the Simmons Comprehensive Cancer Center, which is supported in part by the National Cancer Institute under award number P30 CA142543. We acknowledge the assistance of the Preclinical Radiation Core Facility, which is supported by CPRIT (RP180770). We thank Dr. Ralph DeBerardinis's guidance, Dr. Lei Bao and Prof. Weibo Luo for the ChIP technical support and MLL-C antibody sharing, Dr. Xiang Cheng and Prof. Deliang Guo for providing the DGAT1 shRNA/sgRNA plasmids, Dr. Jaeil Han and Prof. Joshua Mendell for providing ZSWIM8 plasmid, and Dr. Sabine Lang and Prof. Qin Yan for providing the MLLs antibodies. We also want to thank the kidney cancer patients for donating their tissues for this study. Conception and design, J.Z. and Q.Z.; data acquisition, J.Z. V.T.T. W.M.H. J.Y. J.B. and Q.Z.; analysis and interpretation of data, J.Z. J.M.S. A.H. H.Z. L.J. P.K. R.E. and Q.Z.; writing, review, and/or revision of the manuscript, J.Z. J.M.S. G.Z. L.J. W.M.H. D.N. J.B. and Q.Z.; administrative, technical, or material support, J.Z. G.Z. C.Z. L.H. C.L. X.L. W.M.H. V.T.T. D.N. J.B. and Q.Z.; study supervision, J.B. and Q.Z. The authors declare no competing interests. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as living with a disability. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = aug,
day = "18",
doi = "10.1016/j.molcel.2022.06.003",
language = "English (US)",
volume = "82",
pages = "3030--3044.e8",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "16",
}