Selective inhibition of HDAC6 promotes bladder cancer radiosensitization and mitigates the radiation-induced CXCL1 signalling.
Selective inhibition of HDAC6 promotes bladder cancer radiosensitization and mitigates the radiation-induced CXCL1 signalling.
复制标题
DOI：
10.1038/s41416-023-02195-0
复制
发表时间：
2023-05
影响因子：
8.8
通讯作者：
Su, Sheng-Fang
中科院分区：
文献类型：
--
作者：
Tsai, Yu-Chieh;Wang, Tzu-Yin;Hsu, Chia-Lang;Lin, Wei-Chou;Chen, Jyun-Yu;Li, Jia-Hua;Pu, Yeong-Shiau;Cheng, Ann-Lii;Cheng, Jason Chia-Hsien;Su, Sheng-Fang
虽然三模式治疗切除肿瘤，其次是放化疗出现的肌肉浸润性膀胱癌（MIBC），化疗产生毒性。组蛋白去乙酰化酶抑制剂已被确定为增强癌症放疗（RT）的有效策略。本研究通过转录组学分析和机制研究，探讨HDAC 6在乳腺癌放射敏感性中的作用及其特异性抑制作用。HDAC 6敲低或HDAC 6抑制剂（HDAC 6 i）tubacin发挥放射增敏作用，包括降低克隆形成存活率，增加H3 K9 ac和α-微管蛋白乙酰化，以及积累γ H2 AX，这与panobinostat（一种pan-HDACi）对辐照BC细胞的作用相似。照射下shHDAC 6转导的T24的转录组学显示，shHDAC 6抵消了RT诱导的CXCL 1、SERPINE 1、SDC 1和SDC 2的mRNA表达，这些mRNA表达与细胞迁移、血管生成和转移有关。此外，tubacin显着抑制RT诱导的CXCL 1和辐射增强的侵袭/迁移，而帕比司他升高RT诱导的CXCL 1表达和侵袭/迁移能力。这种表型被抗CXCL 1抗体显著消除，表明CXCL 1的关键调节因子导致BC恶性肿瘤。对尿路上皮癌患者肿瘤的免疫组化评价支持CXCL 1高表达与生存率降低之间的相关性。与泛HDACi不同，选择性HDAC 6 i可以增强BC放射增敏作用，并有效抑制RT诱导的致癌CXCL 1-Snail信号传导，从而进一步提高其与RT的治疗潜力。
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.
登录
查看更多内容
影响因子：
5.2
作者：
Li R;Wen A;Lin J
通讯作者：
Lin J
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
9
作者：
Cao J;Lv W;Wang L;Xu J;Yuan P;Huang S;He Z;Hu J
通讯作者：
Hu J
影响因子：
5.7
作者：
Gupta S;Albertson DJ;Parnell TJ;Butterfield A;Weston A;Pappas LM;Dalley B;O'Shea JM;Lowrance WT;Cairns BR;Schiffman JD;Sharma S
通讯作者：
Sharma S
影响因子：
5.4
作者：
Hassan, Hebatallah;Greve, Burkhard;Goette, Martin
通讯作者：
Goette, Martin