虽然采用切除肿瘤后进行化学放射疗法的三联疗法已经被用于治疗肌层侵袭性膀胱癌(MIBC)，但化疗会产生毒性。已经发现组蛋白去乙酰化酶抑制剂是增强肿瘤放疗(RT)的有效策略。我们通过转录组分析和机制研究研究了HDAC6及其特定抑制对BC射线敏感性的作用。HDAC6敲除或HDAC6抑制剂(如tubacin)均表现出增加放射线敏感性的效果，包括减少集落生成生存力，增加H3K9ac和α-管蛋白乙酰化，累积γH2AX等。这与全HDAC抑制剂panobinostat在辐射BC细胞上的效果类似。shHDAC6转染的T24在放疗下的转录组数据显示，shHDAC6抵消了辐射所致CXCL1、SERPINE1、SDC1和SDC2等与细胞迁移、血管生成和转移有关的mRNA表达。此外，tubacin显著抑制了辐照诱导的CXCL1和辐射增强的侵袭/迁移，而panobinostat增强了辐照诱导的CXCL1表达和侵袭/迁移能力。抗CXCL1抗体明显减弱了这种表型，说明CXCL1是BC恶性程度的关键调节因子。来自膀胱癌患者瘤体的免疫组织化学评估支持高表达CXCL1与存活率降低之间的相关性。与全HDAC抑制剂不同，选择性HDAC6抑制剂能够增强BC的放疗敏感性，并有效抑制RT所致的致癌CXCL1-Snail信号通路，从而进一步提高其与放疗联合治疗的治疗潜力。©2023年作者。

Although trimodality therapy resecting tumours followed by chemoradiotherapy is emerged for muscle-invasive bladder cancer (MIBC), chemotherapy produces toxicities. Histone deacetylase inhibitors have been identified as an effective strategy to enhance cancer radiotherapy (RT).We examined the role of HDAC6 and specific inhibition of HDAC6 on BC radiosensitivity by performing transcriptomic analysis and mechanism study.HDAC6 knockdown or HDAC6 inhibitor (HDAC6i) tubacin exerted a radiosensitizing effect, including decreased clonogenic survival, increased H3K9ac and α-tubulin acetylation, and accumulated γH2AX, which are similar to the effect of panobinostat, a pan-HDACi, on irradiated BC cells. Transcriptomics of shHDAC6-transduced T24 under irradiation showed that shHDAC6 counteracted RT-induced mRNA expression of CXCL1, SERPINE1, SDC1 and SDC2, which are linked to cell migration, angiogenesis and metastasis. Moreover, tubacin significantly suppressed RT-induced CXCL1 and radiation-enhanced invasion/migration, whereas panobinostat elevated RT-induced CXCL1 expression and invasion/migration abilities. This phenotype was significantly abrogated by anti-CXCL1 antibody, indicating the key regulator of CXCL1 contributing to BC malignancy. Immunohistochemical evaluation of tumours from urothelial carcinoma patients supported the correlation between high CXCL1 expression and reduced survival.Unlike pan-HDACi, the selective HDAC6i can enhance BC radiosensitization and effectively inhibit RT-induced oncogenic CXCL1-Snail-signalling, thus further advancing its therapeutic potential with RT.© 2023. The Author(s).