Data from Transcriptional Repression of SIRT3 Potentiates Mitochondrial Aconitase Activation to Drive Aggressive Prostate Cancer to the Bone

• DOI: 10.1158/0008-5472.c.6512733.v1
• Publication Date: 2023-03-31T21:30:13Z
• Authors: Abhisha Sawant De...; Mayrel Palestino ...; Uan-I Chen; John Hasper; Christian Prechtl; Cuijuan Yu; Eriko Katsuta; Tao Dai; Bokai Zhu; Sung Yun Jung; Nagireddy Putluri; Kazuaki Takabe; Xiang H.-F. Zhang; Bert W. O'Malley; Subhamoy Dasgupta
• Keywords: SIRT3

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