The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses

Zhiping Li, Xuanmao Jiao, A. Gordon Robertson, Gabriele Di Sante, Anthony W. Ashton, Agnese DiRocco, Min Wang, Jun Zhao, Sankar Addya, Chenguang Wang, Peter A. McCue, Andrew P. South, Carlos Cordon-Cardo, Runzhi Liu, Kishan Patel, Rasha Hamid, Jorim Parmar, James B. DuHadaway, Steven J.M. Jones, Mathew C. CasimiroNikolaus Schultz, Andrew Kossenkov, Lai Yee Phoon, Hao Chen, Li Lan, Yunguang Sun, Kenneth A. Iczkowski, Hallgeir Rui, Richard G. Pestell

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFβ activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFβ kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.

Original languageEnglish
Pages (from-to)1857-1873
Number of pages17
JournalOncogene
Volume42
Issue number22
DOIs
StatePublished - Jun 2 2023
Externally publishedYes

Keywords

  • DNA Damage/genetics
  • Eye Proteins/metabolism
  • Humans
  • Male
  • Prostate/metabolism
  • Prostatic Intraepithelial Neoplasia/genetics
  • Prostatic Neoplasms/drug therapy
  • Transcription Factors/genetics
  • Transforming Growth Factor beta/genetics

Fingerprint

Dive into the research topics of 'The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses'. Together they form a unique fingerprint.

Cite this