Wang Ziwei, Chen Kunying, Zhang Ke, He Kaihong, Zhang Duoduo, Guo Xiaohan, Huang Tongwen, Hu Jielun, Zhou Xingtao, Nie Shaoping
State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China.
State Key Laboratory of Food Science and Technology, China-Canada Joint Laboratory of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China.
Carbohydr Polym. 2023 Nov 1;319:121208. doi: 10.1016/j.carbpol.2023.121208. Epub 2023 Jul 17.
Inducing lysosomal dysfunction is emerging as a promising means for cancer therapy. Agrocybe cylindracea fucoglucogalactan (ACP) is a bioactive ingredient with anti-tumor activity, while its mechanism remains obscure. Herein, we found that ACP visibly inhibited the proliferation of colorectal cancer cells, and the IC50 value on HCT-116 cells (HT29 cells) was 490 μg/mL (786.4 μg/mL) at 24 h. RNA-seq showed that ACP regulated mitochondria, lysosome and apoptosis-related pathways. Further experiments proved that ACP indeed promoted apoptosis and lysosomal dysfunction of HCT-116 cells. Moreover, ChIP-seq revealed that ACP increased histone-H3-lysine-27 acetylation (H3K27ac) on CTSD (cathepsin D) promoter in HCT-116 cells, thus facilitating the binding of transcription factor EB (TFEB), and resulted in ascension of CTSD expression. Additionally, ACP triggered mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential and increasing pro-apoptotic protein levels. Notably, Pepstatin A (CTSD inhibitor) availably alleviated ACP-induced apoptosis. Taken together, our results indicated that ACP induced lysosome-mitochondria mediated apoptosis via H3K27ac-regulated CTSD in HCT-116 cells. This study indicates that ACP has anti-cancer potential in the treatment of colorectal cancer.
诱导溶酶体功能障碍正成为一种有前景的癌症治疗手段。柱状田头菇岩藻糖葡萄糖半乳糖聚糖（ACP）是一种具有抗肿瘤活性的生物活性成分，但其作用机制仍不清楚。在此，我们发现ACP明显抑制结肠癌细胞的增殖，在24小时时对HCT-116细胞（HT29细胞）的IC50值为490μg/mL（786.4μg/mL）。RNA测序表明ACP调节线粒体、溶酶体和凋亡相关途径。进一步实验证明，ACP确实促进了HCT-116细胞的凋亡和溶酶体功能障碍。此外，染色质免疫沉淀测序显示，ACP增加了HCT-116细胞中组织蛋白酶D（CTSD）启动子上的组蛋白-H3-赖氨酸-27乙酰化（H3K27ac），从而促进转录因子EB（TFEB）的结合，并导致CTSD表达升高。此外，ACP通过降低线粒体膜电位和增加促凋亡蛋白水平触发线粒体介导的凋亡。值得注意的是，胃蛋白酶抑制剂A（CTSD抑制剂）可有效减轻ACP诱导的凋亡。综上所述，我们的结果表明，ACP在HCT-116细胞中通过H3K27ac调节的CTSD诱导溶酶体-线粒体介导的凋亡。本研究表明，ACP在结直肠癌治疗中具有抗癌潜力。
