Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis

Alessandro Carrer, Sophie Trefely, Steven Zhao, Sydney L. Campbell, Robert J. Norgard, Kollin C. Schultz, Simone Sidoli, Joshua L.D. Parris, Hayley C. Affronti, Sharanya Sivanand, Shaun Egolf, Yogev Sela, Marco Trizzino, Alessandro Gardini, Benjamin A. Garcia, Nathaniel W. Snyder, Ben Z. Stanger, Kathryn E. Wellen

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS-mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA–producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT–ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA–dependent processes exerts anticancer effects. SIGNIFICANCE : Pancreatic cancer is among the deadliest of human malignancies. We identify a key role for the metabolic enzyme ACLY, which produces acetyl-CoA, in pancreatic carcinogenesis. The data suggest that acetyl-CoA use for histone acetylation and in the mevalonate pathway facilitates cell plasticity and proliferation, suggesting potential to target these pathways.

Original languageEnglish (US)
Pages (from-to)416-435
Number of pages20
JournalCancer discovery
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Oncology

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    Carrer, A., Trefely, S., Zhao, S., Campbell, S. L., Norgard, R. J., Schultz, K. C., Sidoli, S., Parris, J. L. D., Affronti, H. C., Sivanand, S., Egolf, S., Sela, Y., Trizzino, M., Gardini, A., Garcia, B. A., Snyder, N. W., Stanger, B. Z., & Wellen, K. E. (2019). Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer discovery, 9(3), 416-435. https://doi.org/10.1158/2159-8290.CD-18-0567