p300/YY1/miR-500a-5p/HDAC2 信号轴调控人结直肠癌细胞增殖。
The p300/YY1/miR-500a-5p/HDAC2 signalling axis regulates cell proliferation in human colorectal cancer.
机构信息
Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
出版信息
Nat Commun. 2019 Feb 8;10(1):663. doi: 10.1038/s41467-018-08225-3.
The biological role of miR-500a-5p has not yet been reported in the context of colorectal cancer (CRC). Here, we show that miR-500a-5p expression is decreased in CRC tissues compared with adjacent normal tissues. Low miR-500a-5p expression is associated with malignant progression. Moreover, transfection of CRC cells with miR-500a-5p induces G0/G1 cell cycle arrest and inhibits their growth and migration. Mechanistically, miR-500a-5p directly targets HDAC2 and inhibits HDAC2-mediated proliferation in CRC in nude mice. Furthermore, YY1 binds to the promoter of miR-500a-5p and negatively regulates its transcription. Restoration of miR-500a-5p expression is up-regulated via the p300/YY1/HDAC2 complex. Besides, therapeutic delivery of miR-500a-5p significantly suppresses tumour development in a xenograft tumour model and a HDAC2 inhibitor FK228-treated CRC model. Our studies demonstrate that miR-500a-5p functions as a tumour suppressor in CRC by targeting the p300/YY1/HDAC2 axis, which contributes to the development of and provides new potential candidates for CRC therapy.
miR-500a-5p 在结直肠癌（CRC）中的生物学作用尚未见报道。在这里，我们发现与相邻正常组织相比，CRC 组织中 miR-500a-5p 的表达降低。低表达 miR-500a-5p 与恶性进展有关。此外，miR-500a-5p 转染 CRC 细胞可诱导 G0/G1 细胞周期停滞，并抑制其生长和迁移。机制上，miR-500a-5p 可直接靶向 HDAC2 并抑制 CRC 裸鼠中 HDAC2 介导的增殖。此外，YY1 结合 miR-500a-5p 的启动子并负调控其转录。通过 p300/YY1/HDAC2 复合物可上调 miR-500a-5p 的表达恢复。此外，miR-500a-5p 的治疗性传递可显著抑制异种移植肿瘤模型和 HDAC2 抑制剂 FK228 处理的 CRC 模型中的肿瘤发展。我们的研究表明，miR-500a-5p 通过靶向 p300/YY1/HDAC2 轴在 CRC 中发挥肿瘤抑制作用，这有助于 CRC 的发展，并为 CRC 治疗提供了新的潜在候选药物。
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