Acetyl-CoA Synthetase 2: A Critical Linkage in Obesity-Induced Tumorigenesis in Myeloma

Zongwei Li, Huan Liu, Jin He, Zhiqiang Wang, Zheng Yin, Gichun You, Zhiming Wang, Richard E. Davis, Pei Lin, P. Leif Bergsagel, Elisabet E. Manasanch, Stephen T.C. Wong, Nestor F. Esnaola, Jenny C. Chang, Robert Z. Orlowski, Qing Yi, Jing Yang

Research output: Contribution to journalArticlepeer-review

Abstract

Obesity is often linked to malignancies including multiple myeloma, and the underlying mechanisms remain elusive. Here we showed that acetyl-CoA synthetase 2 (ACSS2) may be an important linker in obesity-related myeloma. ACSS2 is overexpressed in myeloma cells derived from obese patients and contributes to myeloma progression. We identified adipocyte-secreted angiotensin II as a direct cause of adiposity in increased ACSS2 expression. ACSS2 interacts with oncoprotein interferon regulatory factor 4 (IRF4), and enhances IRF4 stability and IRF4-mediated gene transcription through activation of acetylation. The importance of ACSS2 overexpression in myeloma is confirmed by the finding that an inhibitor of ACSS2 reduces myeloma growth both in vitro and in a diet-induced obese mouse model. Our findings demonstrate a key impact for obesity-induced ACSS2 on the progression of myeloma. Given the central role of ACSS2 in many tumors, this mechanism could be important to other obesity-related malignancies.

Original languageEnglish (US)
Pages (from-to)78-93.e7
JournalCell Metabolism
Volume33
Issue number1
DOIs
StatePublished - Jan 5 2021

Keywords

  • ACSS2
  • adipocytes
  • angiotensin II
  • autophagy
  • IRF4
  • lysine acetylation
  • multiple myeloma
  • obesity

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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