HMG-CoA synthase 1 is a synthetic lethal partner of BRAF(V600E) in human cancers

• Type of Material: Article
• Authors: Liang Zhao, Emory University; Jun Fan, Emory University; Siyuan Xia, Emory University; Yaozhu Pan, Emory University; Shuangping Liu, Emory University; Guoqing Qian, Emory University; Zhiyu Qian, Emory University; Hee-Bum Kang, Emory University; Jack Arbiser, Emory University; Brian P Pollack, Emory University; Ragini R. Kudchadkar, Emory University; David H Lawson, Emory University; Michael R Rossi, Emory University; Omar Abdel-Wahab, Memorial Sloan-Kettering Cancer Center; Taha Merghoub, Memorial Sloan-Kettering Cancer Center; H Jean Khoury, Emory University; Fadlo Khuri, Emory University; Lawrence Boise, Emory University; Sagar Lonial, Emory University; Fangping Chen, Xiangya Hospital; Jing Chen, Emory University; Ruiting Lin, Emory University
• Language: English
• Date: 2017-06-16
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M117.788778
• Title of Journal or Parent Work: Journal of Biological Chemistry
• Volume: 292
• Issue: 24
• Start Page: 10142
• End Page: 10152
• Grant/Funding Information: This work was supported in part by National Institutes of Health Grants CA140515, CA183594, CA174786 (J.C.), and AR47901 (J.L.A.); Joel A. Katz Music Medicine Fund supported by the T.J. Martell Foundation/Winship Cancer Institute (J.C. and R.L.); the Jamie Rabinowitch-Davis Foundation for Melanoma Research (J.L.A.); the Charles Harris Run For Leukemia, Inc. (H.J.K.); and the Melanoma Research Foundation and the Winship Cancer Institute Melanoma & Skin Cancer Fund (B.P.P.).
• Keywords: KETOGENESIS; BRAF V600E MUTATION; Life Sciences & Biomedicine; DISEASE; MELANOMA; Science & Technology; Biochemistry & Molecular Biology; KETONE-BODY METABOLISM
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Contributions of metabolic changes to cancer development and maintenance have received increasing attention in recent years. Although many human cancers share similar metabolic alterations, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Using an RNAi-based screen targeting the majority of the known metabolic proteins, we recently found that oncogenic BRAFV600Eupregulates HMG-CoA lyase (HMGCL), which converts HMGCoA to acetyl-CoA and a ketone body, acetoacetate, that selectively enhances BRAFV600E-dependent MEK1 activation in human cancer. Here, we identified HMG-CoA synthase 1 (HMGCS1), the upstream ketogenic enzyme of HMGCL, as an additional "synthetic lethal" partner of BRAFV600E. Although HMGCS1 expression did not correlate with BRAFV600Emutation in human melanoma cells, HMGCS1 was selectively important for proliferation of BRAFV600E-positive melanoma and colon cancer cells but not control cells harboring active N/KRAS mutants, and stable knockdown of HMGCS1 only attenuated colony formation and tumor growth potential of BRAFV600Emelanoma cells. Moreover, cytosolic HMGCS1 that co-localized with HMGCL and BRAFV600Ewas more important than the mitochondrial HMGCS2 isoform in BRAFV600E-expressing cancer cells in terms of acetoacetate production. Interestingly, HMGCL knockdown did not affect HMGCS1 expression levels, whereas HMGCS1 knockdown caused a compensating increase in HMGCL protein level because of attenuated protein degradation. However, this increase did not reverse the reduced ketogenesis in HMGCS1 knockdown cells. Mechanistically, HMGCS1 inhibition decreased intracellular acetoacetate levels, leading to reduced BRAFV600E-MEK1 binding and consequent MEK1 activation. We conclude that the ketogenic HMGCS1-HMGCL-acetoacetate axis may represent a promising therapeutic target for managing BRAFV600E-positive human cancers.