Selective inhibition of HDAC6 promotes bladder cancer radiosensitization and mitigates the radiation-induced CXCL1 signalling

by Selleckchem | Mar 20 2023

Background: 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).

Methods: We examined the role of HDAC6 and specific inhibition of HDAC6 on BC radiosensitivity by performing transcriptomic analysis and mechanism study.

Results: 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.

Conclusion: 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.

Comments：

In this study, the researchers investigated the potential of using histone deacetylase 6 (HDAC6) inhibitors as a strategy to enhance the radiosensitivity of bladder cancer (BC) cells. They found that HDAC6 knockdown or inhibition using the HDAC6 inhibitor tubacin resulted in a radiosensitizing effect, similar to the pan-HDAC inhibitor panobinostat, which is commonly used in the treatment of BC. This effect was characterized by decreased clonogenic survival, increased acetylation of histone H3 lysine 9 (H3K9ac) and α-tubulin, and increased accumulation of γH2AX, a marker of DNA damage.

The researchers also performed transcriptomic analysis and found that HDAC6 knockdown counteracted the radiation-induced expression of several genes, including CXCL1, SERPINE1, SDC1, and SDC2, which are involved in cell migration, angiogenesis, and metastasis. They further demonstrated that tubacin was able to suppress radiation-induced CXCL1 expression and invasion/migration, while panobinostat increased these effects. The researchers also showed that CXCL1 is a key regulator contributing to BC malignancy and that high CXCL1 expression is correlated with reduced survival in urothelial carcinoma patients.

Overall, these findings suggest that selective HDAC6 inhibition can enhance BC radiosensitization and effectively inhibit radiation-induced oncogenic signaling, making it a promising therapeutic strategy to be used in combination with radiation therapy for the treatment of BC.