Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; Departments of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Departments of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Metab. 2021 Jan 5;33(1):78-93.e7. 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.
肥胖症通常与多种骨髓瘤有关，但其潜在机制仍难以捉摸。在这里，我们表明乙酰辅酶 A 合成酶 2（ACSS2）可能是肥胖相关骨髓瘤的重要连接物。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 与致癌蛋白干扰素调节因子 4（IRF4）相互作用，并通过激活乙酰化来增强 IRF4 的稳定性和 IRF4 介导的基因转录。ACSS2 在骨髓瘤中的过度表达的重要性通过发现 ACSS2 的抑制剂可减少体外和饮食诱导肥胖小鼠模型中的骨髓瘤生长得到证实。我们的研究结果表明，肥胖诱导的 ACSS2 对骨髓瘤的进展有重要影响。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也很重要。
