부산대학교 도서관

Simple Summary: A significant number of prostate cancers (PC) recur in patients despite treatment with chemotherapy or radiotherapy. While HOXB13 contributes to resistance to anti-androgen treatment, its role in radio resistance is unknown. Herein, we show that HOXB13 assembles at DNA damage sites and colocalizes with γH2AX at double strand breaks despite Androgen Receptor antagonism. Functionally, ablation of HOXB13 sensitizes PC cells to either radiotherapy or anti-androgen Enzalutamide as well as combination therapies. Resistance to these agents is mediated by acetylation of HOXB13 at lysine 13, which acts as an interaction module for the Switch deficient Sucrose Nonfermenting (SWI/SNF) chromatin remodeling complex. K13-acetylated HOXB13 is required for effective DNA replication following DNA damage and for the formation of nuclear puncta. Our results reveal a hitherto unknown but critical role for HOXB13 in ensuring genomic integrity in PC. 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, targeting HOXB13 acetylation with CBP/p300 inhibitors in combination with DNA damaging therapy may be an effective strategy to overcome anti-androgen resistance of PCs. [ABSTRACT FROM AUTHOR]