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Updated: Jun 26, 2025

Author Spotlight: Combining Proximity Ligand Assay with Gamma-H2AX Staining to Characterize Protein Interactions in DNA Damage Response
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Author Spotlight: Combining Proximity Ligand Assay with Gamma-H2AX Staining to Characterize Protein Interactions in DNA Damage Response

Published on: August 2, 2024

472

Amino Terminal Acetylation of HOXB13 Regulates the DNA Damage Response in Prostate Cancer

Duy T Nguyen1,2, Urvashi Mahajan1,3, Duminduni Hewa Angappulige1

  • 1Division of Urologic Surgery, Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.

Cancers
|May 11, 2024
PubMed

Insights

Acetylated HOXB13 promotes prostate cancer survival after DNA damage. Targeting HOXB13 acetylation may overcome resistance to anti-androgen therapies and improve treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Advanced prostate cancer (PC) often recurs despite standard treatments like chemotherapy, radiotherapy, and androgen deprivation therapy.
  • HOXB13 lysine (K)13 acetylation was previously identified as a gain-of-function modification crucial for anti-androgen resistance in PC.
  • The role of acetylated HOXB13 in promoting PC cell survival following genotoxic stress remained unexplored.

Purpose of the Study:

  • To investigate whether K13-acetylated HOXB13 promotes prostate cancer cell survival after DNA damage.
  • To elucidate the mechanism by which HOXB13 acetylation influences DNA damage response and treatment resistance.

Main Methods:

  • Induction of K13-acetylated HOXB13 in PC cells upon irradiation (IR) and its colocalization with γH2AX at double-strand break (DSB) sites.
  • Assessment of HOXB13 acetylation status in PC cells treated with Enzalutamide (ENZ) and IR.
  • Evaluation of HOXB13 depletion or acetylation loss on PC cell resistance to ENZ and synergy with IR.
  • Analysis of HOXB13 K13A mutants' effects on DNA damage response, including replication fork progression and G2/M arrest.

Main Results:

  • K13-acetylated HOXB13 is rapidly induced in PC cells following IR-induced DNA damage, localizing to DSBs.
  • Enzalutamide (ENZ) treatment did not inhibit DNA-damage-induced HOXB13 acetylation.
  • HOXB13 depletion or loss of acetylation sensitized PC cells to ENZ and synergized with IR.
  • HOXB13 K13A mutants exhibited impaired DNA damage response, including reduced replication fork progression and G2/M arrest, leading to significant cell death.

Conclusions:

  • K13-acetylated HOXB13 plays a critical role in promoting PC cell survival and resistance to anti-androgen therapy, particularly following DNA damage.
  • Targeting HOXB13 acetylation, potentially with CBP/p300 inhibitors, in combination with DNA-damaging agents, represents a promising therapeutic strategy for overcoming treatment resistance in advanced prostate cancer.
Keywords:
CBP/p300DNA damageHOXB13acetylationcondensateprostate cancerradio resistance

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