Inhibition of HDAC2 sensitises antitumour therapy by promoting NLRP3/GSDMD‐mediated pyroptosis in colorectal cancer

作者：Xin Guan, Ruiqi Liu, Bojun Wang, Rui Xiong, Luying Cui, Yuanyu Liao, Yuli Ruan, Lin Fang, Xiaolin Lü, Xuefan Yu, Dan Su, Yue Ma, Tianjiao Dang, Zhuo Chen, Yuanfei Yao, Chao Liu, Yanqiao Zhang · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.1692 · 被引用次数：51 · 研究领域：Inflammasome and immune disorders、Immune cells in cancer、Inflammatory Biomarkers in Disease Prognosis

BACKGROUND: Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis in colorectal cancer (CRC) remains unclear. METHODS: Pyroptosis in CRC cells treated with antitumour agents was assessed using various techniques, including Western blotting, lactate dehydrogenase release assay and microscopy analysis. To uncover the epigenetic mechanisms that regulate NLRP3, chromatin changes and NLRP3 promoter histone modifications were assessed using Assay for Transposase-Accessible Chromatin using sequencing and RNA sequencing. Chromatin immunoprecipitation‒quantitative polymerase chain reaction was used to investigate the NLRP3 transcriptional regulatory mechanism. Additionally, xenograft and patient-derived xenograft models were constructed to validate the effects of the drug combinations. RESULTS: As the core molecule of the inflammasome, NLRP3 expression was silenced in CRC, thereby limiting gasdermin D (GSDMD)-mediated pyroptosis. Supplementation with NLRP3 can rescue pyroptosis induced by antitumour therapy. Overexpression of HDAC2 in CRC silences NLRP3 via epigenetic regulation. Mechanistically, HDAC2 suppressed chromatin accessibility by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac-mediated recruitment of the BRD4-p-P65 complex to enhance NLRP3 transcription. Inhibiting HDAC2 by Santacruzamate A in combination with classic antitumour agents (5-fluorou...