Cell Metabolism ( IF 29.0 ) Pub Date : 2021-01-05 , DOI: 10.1016/j.cmet.2020.12.011 Zongwei Li 1 , Huan Liu 1 , Jin He 1 , Zhiqiang Wang 2 , Zheng Yin 3 , Gichun You 1 , Zhiming Wang 1 , Richard E Davis 2 , Pei Lin 4 , P Leif Bergsagel 5 , Elisabet E Manasanch 2 , Stephen T C Wong 3 , Nestor F Esnaola 6 , Jenny C Chang 6 , Robert Z Orlowski 2 , Qing Yi 6 , Jing Yang 1
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.
中文翻译:
乙酰辅酶 A 合成酶 2:肥胖诱导的骨髓瘤肿瘤发生的关键联系
肥胖通常与包括多发性骨髓瘤在内的恶性肿瘤有关,其潜在机制仍然难以捉摸。在这里,我们发现乙酰辅酶 A 合成酶 2 (ACSS2) 可能是肥胖相关骨髓瘤的重要接头。ACSS2 在源自肥胖患者的骨髓瘤细胞中过度表达,并有助于骨髓瘤的进展。我们确定脂肪细胞分泌的血管紧张素 II 是导致 ACSS2 表达增加的肥胖的直接原因。ACSS2 与癌蛋白干扰素调节因子 4 (IRF4) 相互作用,并通过激活乙酰化增强 IRF4 稳定性和 IRF4 介导的基因转录。ACSS2 抑制剂在体外降低骨髓瘤生长的发现证实了 ACSS2 过表达在骨髓瘤中的重要性在饮食诱导的肥胖小鼠模型中。我们的研究结果证明了肥胖诱导的 ACSS2 对骨髓瘤进展的关键影响。鉴于 ACSS2 在许多肿瘤中的核心作用,这种机制可能对其他与肥胖相关的恶性肿瘤很重要。