Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 (SIRT3) by androgen receptor (AR) and its coregulator steroid receptor coactivator (SRC-2) enhances mitochondrial aconitase (ACO2) activity to favor aggressive prostate cancer. ACO2 promoted mitochondrial citrate synthesis to facilitate de novo lipogenesis, and genetic ablation of ACO2 reduced total lipid content and severely repressed in vivo 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 (HDAC2) to the SIRT3 promoter, and depletion of SRC-2 enhanced SIRT3 expression and simultaneously reduced acetylated-ACO2. In human prostate tumors, ACO2 activity was significantly elevated and increased expression of SRC-2 with concomitant reduction of SIRT3 was found to be a genetic hallmark enriched in prostate cancer metastatic lesions. In a mouse model of spontaneous bone metastasis, suppression of SRC-2 reactivated SIRT3 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.
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PMID:Transcriptional repression of SIRT3 potentiates mitochondrial aconitase activation to drive aggressive prostate cancer to the bone. 3311 5


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