Acetyl-CoA synthetase 2: a critical linkage in obesity-induced tumorigenesis in myeloma

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. To investigate the potential abnormalities of myeloma cells in the obese setting, CD138+ malignant plasma cells were purified from the bone marrow aspirates of 9 newly diagnosed myeloma patients with newly diagnosed myeloma. Total RNA was extracted and used for comparing the gene expression profile between patients with normal weights (BMI < 25 kg/m2, n=4) and obese patients (BMI > 30 kg/m2, n=5).