Transcriptional repression of SIRT3 potentiates mitochondrial aconitase activation to drive aggressive prostate cancer to the bone

Abstract

Metabolic dysregulation is a known hallmark of cancer progression, yet the oncogenic signals that promote metabolic adaptations to drive metastatic cancer remain unclear. Here, we show that transcriptional repression of mitochondrial deacetylase sirtuin 3 (<i>SIRT3</i>) by androgen receptor (AR) and its coregulator steroid receptor coactivator-2 (SRC-2) enhances mitochondrial aconitase (ACO2) activity to favor aggressive prostate cancer. ACO2 promoted mitochondrial citrate synthesis to facilitate <i>de novo</i> lipogenesis, and genetic ablation of <i>ACO2</i> reduced total lipid content and severely repressed <i>in vivo</i> prostate cancer progression. A single acetylation mark lysine258 on ACO2 functioned as a regulatory motif, and the acetylation-deficient Lys258Arg mutant was enzymatically inactive and failed to rescue growth of ACO2-deficient cells. Acetylation of ACO2 was reversibly regulated by SIRT3, which was predominantly repressed in many tumors including prostate cancer. Mechanistically, SRC-2-bound AR formed a repressive complex by recruiting histone deacetylase 2 to the <i>SIRT3</i> promoter, and depletion of <i>SRC-2</i> enhanced <i>SIRT3</i> expression and simultaneously reduced acetylated ACO2. In human prostate tumors, ACO2 activity was significantly elevated, and increased expression of <i>SRC-2</i> with concomitant reduction of <i>SIRT3</i> was found to be a genetic hallmark enriched in prostate cancer metastatic lesions. In a mouse model of spontaneous bone metastasis, suppression of <i>SRC-2</i> reactivated <i>SIRT3</i> expression and was sufficient to abolish prostate cancer colonization in the bone microenvironment, implying this nuclear-mitochondrial regulatory axis is a determining factor for metastatic competence. SIGNIFICANCE: This study highlights the importance of mitochondrial aconitase activity in the development of advanced metastatic prostate cancer and suggests that blocking SRC-2 to enhance <i>SIRT3</i> expression may be therapeutically valuable. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/1/50/F1.large.jpg.