Cancers, Vol. 16, Pages 1622: Amino Terminal Acetylation of HOXB13 Regulates the DNA Damage Response in Prostate Cancer
Cancers, Vol. 16, Pages 1622: Amino Terminal Acetylation of HOXB13 Regulates the DNA Damage Response in Prostate Cancer
Cancers doi: 10.3390/cancers16091622
Authors:
Duy T. Nguyen
Urvashi Mahajan
Duminduni Hewa Angappulige
Aashna Doshi
Nupam P. Mahajan
Kiran Mahajan
Advanced localized prostate cancers (PC) recur despite chemotherapy, radiotherapy and/or androgen deprivation therapy. We recently reported HOXB13 lysine (K)13 acetylation as a gain-of-function modification that regulates interaction with the SWI/SNF chromatin remodeling complex and is critical for anti-androgen resistance. However, whether acetylated HOXB13 promotes PC cell survival following treatment with genotoxic agents is not known. Herein, we show that K13-acetylated HOXB13 is induced rapidly in PC cells in response to DNA damage induced by irradiation (IR). It colocalizes with the histone variant γH2AX at sites of double strand breaks (DSBs). Treatment of PCs with the Androgen Receptor (AR) antagonist Enzalutamide (ENZ) did not suppress DNA-damage-induced HOXB13 acetylation. In contrast, HOXB13 depletion or loss of acetylation overcame resistance of PC cells to ENZ and synergized with IR. HOXB13K13A mutants show diminished replication fork progression, impaired G2/M arrest with significant cell death following DNA damage. Mechanistically, we found that amino terminus regulates HOXB13 nuclear puncta formation that is essential for proper DNA damage response. Therefore, target...
Source: Cancers - Category: Cancer & Oncology Authors: Duy T. Nguyen Urvashi Mahajan Duminduni Hewa Angappulige Aashna Doshi Nupam P. Mahajan Kiran Mahajan Tags: Article Source Type: research