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Transcriptional Repression of SIRT3 Potentiates Mitochondrial Aconitase Activation to Drive Aggressive Prostate

Abhisha Sawant Dessai1, Mayrel Palestino Dominguez1, Uan-I Chen2

  • 1Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Cancer Research
|October 29, 2020
PubMed

Insights

Androgen receptor (AR) and SRC-2 repress SIRT3, boosting ACO2 activity in aggressive prostate cancer. Blocking SRC-2 reactivates SIRT3, inhibiting metastasis and offering a potential therapy.

Area of Science:

  • Molecular Oncology
  • Cancer Metabolism
  • Metastasis Research

Background:

  • Metabolic dysregulation is a hallmark of cancer, but oncogenic signals driving metastatic adaptation are not fully understood.
  • Sirtuin 3 (SIRT3), a mitochondrial deacetylase, plays a role in metabolic regulation, but its repression in cancer and impact on metastasis are unclear.

Purpose of the Study:

  • To investigate the role of androgen receptor (AR), steroid receptor coactivator-2 (SRC-2), and mitochondrial aconitase (ACO2) in prostate cancer progression and metastasis.
  • To elucidate the regulatory axis connecting nuclear signaling (AR/SRC-2) to mitochondrial metabolism (ACO2) and its impact on metastatic competence.

Main Methods:

  • Investigated the transcriptional regulation of SIRT3 by AR and SRC-2.
  • Assessed the enzymatic activity and regulatory acetylation of ACO2.
  • Utilized genetic ablation of ACO2 and depletion of SRC-2 in prostate cancer models.
  • Analyzed human prostate tumor samples for ACO2 activity, SRC-2, and SIRT3 expression.

Main Results:

  • AR and SRC-2 repress SIRT3 expression, leading to increased ACO2 activity, which promotes lipogenesis and prostate cancer progression.
  • Acetylation at Lys258 is crucial for ACO2 activity; SIRT3 deacetylates and regulates ACO2.
  • SRC-2 depletion reactivates SIRT3, reduces acetylated ACO2, and abolishes bone metastasis in a mouse model.

Conclusions:

  • The nuclear-mitochondrial regulatory axis involving AR, SRC-2, SIRT3, and ACO2 is critical for prostate cancer metastatic competence.
  • Elevated ACO2 activity and specific expression patterns of SRC-2 and SIRT3 are hallmarks of metastatic prostate cancer.
  • Therapeutic strategies targeting SRC-2 to enhance SIRT3 expression hold promise for treating metastatic prostate cancer.

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