Acetyl-CoA Synthetase 2 connects obesity and myeloma pathogenesis

The chief function of ACSS2 is the conversion of acetate to acetyl CoA, a metabolite critical in myriad cellular processes to maintain cellular homeostasis. ACSS2 also comes into play under conditions of metabolic stress in cancer cells where it promotes malignant cell growth and survival. The precise role of ACSS2 in myeloma pathogenesis and obesity-induced myeloma progression was hitherto unknown. Data from 2011 to 2016 from the National Program of Cancer Registries and Epidemiology and End Results Program indicate a rising trend in the estimated obesity-related myeloma cases. To understand the influence of host obese conditions on myelomatous tumorigenesis, Yang compared a diet-induced obesity mouse model with control mice to estimate the effects of a high-calorie diet on the tumor burden. Both mouse models were intrafemorally injected with murine myeloma Vk12598 cells and results indicated enhanced incidence and development of multiple myeloma under obese conditions. This conclusion is consistent with previous literature suggesting that an adipocyte-rich microenvironment supports tumor growth. Next, malignant plasma cells from nine newly diagnosed myeloma patients were used to perform microarray gene expression profiling. Comparison of normal weight and obese myeloma patients’ samples led to the identification of 348 genes that are upregulated in myeloma cells of obese patients. Gene ontology analyses further identified inflammatory responses and metabolic processes to be most transformed. Finally, gene set enrichment analyses led Yang to pinpoint the acetyl CoA metabolic process and specifically ACSS1 and ACSS2 to be augmented in samples from obese myeloma patients. The research study led by Yang produced several significant findings. First, it found an elevated ACSS2 expression in malignant plasma cells from myeloma patients. ACSS2 expression was significantly higher in obese myeloma patients and positively correlated with BMI values. Second, ACSS2 in myeloma cells was found to promote myeloma tumorigenesis via stabilization of oncogenic interferon regulatory factor 4 (IRF4) protein. Third, there was an increased ACSS2 expression in myeloma cells of obese patients in response to angiotensin II, a cytokine secreted by adipocytes. Adipose tissues from obese patients produced more angiotensin II, as compared to non-obese patients. This indicated ACSS2 contribution to obesity-induced myeloma tumorigenesis. Supplemental microarray analyses also suggested higher relative expression of ACSS1 and ACSS2 to be correlated with shorter survival in obese myeloma patients. Lastly, as expected from the mechanistic model, inhibition of angiotensin II-ACSS2 induction prevented obesity-induced tumorigenesis. Several previously unknown functions of ACSS2 were uncovered in this study. For instance, Yang identified a critical amino acid lysine 399 on IRF4, which is the site of IRF4 acetylation by ACSS2. The lysine 399 residue was found to be evolutionarily conserved across species suggesting this acetylation event to be an important occurrence in vivo. Moreover, acetylation of IRF4 at lysine 399 precludes IRF4 protein degradation by lysosomes - a modulation significant in myeloma development.