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.HOXB13K13Amutants 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.
尽管经过化疗、放疗和/或雄激素剥夺治疗，晚期局限性前列腺癌（PC）仍会复发。我们近期研究发现，HOXB13赖氨酸（K）13位点的乙酰化作为一种功能获得性修饰，可调控其与SWI/SNF染色质重塑复合物的相互作用，这对抗雄激素耐药至关重要。然而，乙酰化的HOXB13是否能在基因毒性药物治疗后促进PC细胞存活尚不明确。本研究表明，在辐射（IR）诱导DNA损伤时，PC细胞中K13位点乙酰化的HOXB13会迅速被诱导表达。它与组蛋白变体γH2AX共同定位于双链断裂（DSBs）位点。使用雄激素受体（AR）拮抗剂恩杂鲁胺（ENZ）处理PC细胞，并未抑制DNA损伤诱导的HOXB13乙酰化。相反，HOXB13的缺失或乙酰化修饰的消除能够克服PC细胞对ENZ的耐药性，并与IR产生协同作用。HOXB13K13A突变体表现出复制叉进程减缓、G2/M期阻滞受损，并在DNA损伤后出现显著的细胞死亡。机制上，我们发现氨基末端调控HOXB13核斑点的形成，这对正常的DNA损伤应答至关重要。因此，利用CBP/p300抑制剂靶向HOXB13乙酰化，联合DNA损伤疗法，可能成为克服PC抗雄激素耐药的有效策略。
Amino Terminal Acetylation of HOXB13 Regulates the DNA Damage Response in Prostate Cancer
肿瘤(癌症)患者之家