HMG-CoA synthase 1 is a synthetic lethal partner of BRAFV600E 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 up-regulates HMG-CoA lyase (HMGCL), which converts HMG-CoA 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.

• Authors: Liang Zhao, Jun Fan, Siyuan Xia, Yaozhu Pan, Shuangping Liu, Guoqing Qian, Zhiyu Qian, Hee-Bum Kang, Jack L Arbiser, Brian P Pollack, Ragini R Kudchadkar, David H Lawson, Michael Rossi, Omar Abdel-Wahab, Taha Merghoub, Hanna J Khoury, Fadlo R Khuri, Lawrence H Boise, Sagar Lonial, Fangping Chen, Jing Chen, Ruiting Lin
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 24 Pg. 10142-10152 (06 16 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28468827 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Acetoacetates
• Isoenzymes
• Neoplasm Proteins
• acetoacetic acid
• HMGCS1 protein, human
• Hydroxymethylglutaryl-CoA Synthase
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• MAP Kinase Kinase 1
• MAP2K1 protein, human
• Oxo-Acid-Lyases
• 3-hydroxy-3-methylglutaryl-coenzyme A lyase

Topics

• Acetoacetates (metabolism)
• Amino Acid Substitution
• Animals
• Cell Line, Tumor
• Cell Proliferation
• Colonic Neoplasms (enzymology, metabolism, pathology)
• Cytosol (enzymology, metabolism)
• Enzyme Activation
• Enzyme Stability
• Female
• Humans
• Hydroxymethylglutaryl-CoA Synthase (antagonists & inhibitors, genetics, metabolism)
• Isoenzymes (antagonists & inhibitors, genetics, metabolism)
• MAP Kinase Kinase 1 (chemistry, metabolism)
• Melanoma (enzymology, metabolism, pathology)
• Mice, Nude
• Mutation
• Neoplasm Proteins (antagonists & inhibitors, chemistry, genetics, metabolism)
• Neoplasm Transplantation
• Oxo-Acid-Lyases (antagonists & inhibitors, chemistry, genetics, metabolism)
• Proteolysis
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• RNA Interference
• Tumor Burden