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

• Published in: Cell metabolism 2021-01, Vol.33 (1), p.78-93.e7
• Main Authors: Li, Zongwei, Liu, Huan, He, Jin, Wang, Zhiqiang, Yin, Zheng, You, Gichun, Wang, Zhiming, Davis, Richard E., Lin, Pei, Bergsagel, P. Leif, Manasanch, Elisabet E., Wong, Stephen T.C., Esnaola, Nestor F., Chang, Jenny C., Orlowski, Robert Z., Yi, Qing, Yang, Jing
• Format: Article
• Language: English
• Subjects: Acetate-CoA Ligase - genetics; Acetate-CoA Ligase - metabolism; ACSS2; adipocytes; angiotensin II; Animals; autophagy; Female; IRF4; lysine acetylation; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; obesity; Obesity - genetics; Obesity - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2020.12.011

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. [Display omitted] •ACSS2 contributes to obesity-induced myelomatous tumorigenesis•Adipocyte-derived angiotensin II enhances ACSS2 expression in myeloma cells•ACSS2-mediated lysine acetylation improves the stability of oncogenic IRF4 protein•Inhibition of the angiotensin II-ACSS2 axis prevents obesity-induced tumor growth Li et al. demonstrate a mechanistic link between obesity and myeloma. Adipocyte-derived angiotensin II stimulates acetyl-CoA synthase 2 (ACSS2) expression in myeloma cells and increased ACSS2 promotes tumorigenesis through the stabilization of interferon regulatory factor 4. Inhibiting the angiotensin II/ACSS2 axis abolishes obesity-associated myeloma progression, suggesting a potential therapeutic target for obesity-associated tumors.