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Updated: Mar 29, 2026

An Orthotopic Murine Model of Human Prostate Cancer Metastasis
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An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

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HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate

M Ruscetti1,2, E L Dadashian2, W Guo3

  • 1Molecular Biology Institute, UCLA, Los Angeles, CA, USA.

Oncogene
|December 8, 2015
PubMed

Insights

Epigenetic regulation drives prostate cancer's epithelial-mesenchymal transition (EMT) and resistance to therapy. Targeting HMGA2 with LBH589 inhibits EMT, reduces metastasis, and resensitizes resistant cells to treatment.

Area of Science:

  • Oncology
  • Cancer Biology
  • Epigenetics

Background:

  • Coactivation of PI3K/AKT and RAS/MAPK pathways drives prostate cancer progression, including epithelial-mesenchymal transition (EMT) and incurable metastatic castration-resistant prostate cancer (mCRPC).
  • Understanding the dynamic regulation of EMT is crucial for developing effective mCRPC therapies.

Purpose of the Study:

  • To investigate the epigenetic mechanisms regulating EMT and therapeutic resistance in prostate cancer.
  • To evaluate the therapeutic potential of targeting epigenetic regulators, specifically HMGA2, in mCRPC.

Main Methods:

  • Development of novel genetically defined cellular and in vivo models allowing isolation of epithelial, EMT, and mesenchymal-like prostate cancer cells.
  • Assessment of epithelial-mesenchymal plasticity and response to pathway inhibitors.
  • Analysis of epigenetic regulators, including HMGA2, and evaluation of HMGA2 knockdown and inhibition with LBH589 (a histone deacetylase inhibitor).
  • In vivo studies assessing tumor growth, metastasis, and survival following LBH589 treatment alone and in combination with castration.

Main Results:

  • Mesenchymal-like tumor cells, despite identical genetic alterations, exhibit resistance to PI3K and MAPK pathway inhibitors, suggesting epigenetic control.
  • HMGA2 is significantly upregulated in EMT and mesenchymal-like cells and in human mCRPC.
  • HMGA2 knockdown or LBH589 treatment inhibited EMT, reduced stemness, tumor growth, and metastasis in vivo.
  • Combined LBH589 and castration prevented mCRPC development, prolonged survival by enhancing p53 and androgen receptor acetylation, and sensitized resistant cells to androgen deprivation therapy.

Conclusions:

  • Cellular plasticity in mCRPC is epigenetically regulated.
  • Mesenchymal-like tumor cells in mCRPC, resistant to conventional and targeted therapies, can be effectively targeted using the epigenetic inhibitor LBH589.
  • Targeting HMGA2 with LBH589 represents a promising therapeutic strategy for mCRPC, particularly in combination with standard treatments.

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