Acetyl-CoA Synthetase 2: A Critical Linkage in Obesity-Induced Tumorigenesis in Myeloma.
Acetyl-CoA Synthetase 2: A Critical Linkage in Obesity-Induced Tumorigenesis in Myeloma.
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DOI：
10.1016/j.cmet.2020.12.011
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发表时间：
2021-01-05
期刊：
影响因子：
29
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Li Z;Liu H;He J;Wang Z;Yin Z;You G;Wang Z;Davis RE;Lin P;Bergsagel PL;Manasanch EE;Wong STC;Esnaola NF;Chang JC;Orlowski RZ;Yi Q;Yang J
肥胖通常与包括多发性骨髓瘤在内的恶性肿瘤有关，但其潜在机制仍然难以捉摸。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子。 ACSS2 在源自肥胖患者的骨髓瘤细胞中过度表达，并导致骨髓瘤进展。我们发现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，通过乙酰化激活增强 IRF4 稳定性和 IRF4 介导的基因转录。 ACSS2 抑制剂在体外和饮食诱导的肥胖小鼠模型中均可减少骨髓瘤的生长，这一发现证实了 ACSS2 过度表达在骨髓瘤中的重要性。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，这种机制对于其他与肥胖相关的恶性肿瘤可能很重要。李等人。证明肥胖与骨髓瘤之间存在机制联系。脂肪细胞来源的血管紧张素 II 刺激骨髓瘤细胞中乙酰辅酶 A 合酶 2 (ACSS2) 的表达，增加的 ACSS2 通过稳定干扰素调节因子 4 促进肿瘤发生。抑制血管紧张素 II/ACSS2 轴可消除肥胖相关骨髓瘤的进展，这表明肥胖相关肿瘤的潜在治疗靶点。
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), 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. 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.
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影响因子：
28.2
作者：
Incio J;Liu H;Suboj P;Chin SM;Chen IX;Pinter M;Ng MR;Nia HT;Grahovac J;Kao S;Babykutty S;Huang Y;Jung K;Rahbari NN;Han X;Chauhan VP;Martin JD;Kahn J;Huang P;Desphande V;Michaelson J;Michelakos TP;Ferrone CR;Soares R;Boucher Y;Fukumura D;Jain RK
通讯作者：
Jain RK
影响因子：
7.7
作者：
Conery, Andrew R.;Centore, Richard C.;Sims, Robert J., III
通讯作者：
Sims, Robert J., III
影响因子：
6.9
作者：
Hwang, Ling-Ling;Wang, Chien-Hua;Chiou, Lih-Chu
通讯作者：
Chiou, Lih-Chu
影响因子：
3.8
作者：
Chiu, Brian C-H.;Gapstur, Susan M.;Dyerl, Alan
通讯作者：
Dyerl, Alan
影响因子：
158.5
作者：
Calle, EE;Rodriguez, C;Thun, MJ
通讯作者：
Thun, MJ