HMG-CoA synthase 1 is a synthetic lethal partner of BRAF(V600E) in human cancers Journal Article
| Authors: | Zhao, L.; Fan, J.; Xia, S.; Pan, Y.; Liu, S.; Qian, G.; Qian, Z.; Kang, H. B.; Arbiser, J. L.; Pollack, B. P.; Kudchadkar, R. R.; Lawson, D. H.; Rossi, M.; Abdel-Wahab, O.; Merghoub, T.; Khoury, H. J.; Khuri, F. R.; Boise, L. H.; Lonial, S.; Chen, F.; Chen, J.; Lin, R. |
| Article Title: | HMG-CoA synthase 1 is a synthetic lethal partner of BRAF(V600E) in human cancers |
| 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 BRAFV600E upregulates 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 BRAFV600E mutation 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 BRAFV600E melanoma cells. Moreover, cytosolic HMGCS1 that co-localized with HMGCL and BRAFV600E was 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. |
| Keywords: | controlled study; human tissue; protein expression; unclassified drug; human cell; genetics; mutation; cancer growth; nonhuman; cell proliferation; proteins; protein analysis; mouse; animal; cytology; metabolism; animals; animal tissue; melanoma; mitogen activated protein kinase kinase 1; amino acid substitution; tumor volume; protein degradation; neoplasm proteins; animal experiment; animal model; protein binding; colonic neoplasms; rna interference; enzyme activation; enzymology; pathology; cell line, tumor; oncology; chemistry; nude mouse; mice, nude; tumors; tumor burden; colon tumor; tumor protein; tumor cell line; melanoma cell; upregulation; neoplasm transplantation; k ras protein; therapeutic targets; glutamic acid; b raf kinase; dermatology; map kinase kinase 1; diseases; lyase; cytosol; proto-oncogene proteins b-raf; isoenzymes; braf protein, human; valine; ketones; cancer transplantation; chemical activation; cells; enzyme stability; isoenzyme; colony formation; oxo-acid-lyases; expression levels; proteolysis; map2k1 protein, human; attenuation; tumor development; hydroxymethylglutaryl coenzyme a synthase; metabolic changes; humans; human; female; priority journal; article; antagonists and inhibitors; acetoacetic acid; cancer development; colon cancer cells; metabolic proteins; hmg coa synthase 1; 3-hydroxy-3-methylglutaryl-coenzyme a lyase; acetoacetic acid derivative; hmgcs1 protein, human; colon cancer cell line; acetoacetates; hydroxymethylglutaryl-coa synthase |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 292 |
| Issue: | 24 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2017-06-16 |
| Start Page: | 10142 |
| End Page: | 10152 |
| Language: | English |
| DOI: | 10.1074/jbc.M117.788778 |
| PUBMED: | 28468827 |
| PROVIDER: | scopus |
| PMCID: | PMC5473220 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 August 2017 -- Source: Scopus |
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