MORC2 promotes development of an aggressive colorectal cancer phenotype through inhibition of NDRG1.
MORC2 promotes development of an aggressive colorectal cancer phenotype through inhibition of NDRG1.
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MORC2 通过抑制 NDRG1 促进侵袭性结直肠癌表型的发展
DOI：
10.1111/cas.13863
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发表时间：
2019-01
期刊：
影响因子：
5.7
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Liu J;Shao Y;He Y;Ning K;Cui X;Liu F;Wang Z;Li F
MORC2是一种新发现的染色质重塑蛋白，在包括基因转录在内的多种生物过程中发挥作用。NDRG1是一种转移抑制因子和结直肠癌（CRC）的预后生物标志物。然而，MORC2与NDRG1转录调控之间的关系以及MORC2在CRC中的作用仍不清楚。在这里，我们发现MORC2下调了CRC细胞中NDRG1 mRNA、蛋白水平和启动子活性。我们还发现MORC2结合到NDRG1启动子的- 446至- 213 bp区域。机制上，组蛋白去乙酰化酶SIRT1 （SIRT1）参与NDRG1的转录调控。MORC2能够与SIRT1相互作用，并通过SIRT1累积抑制NDRG1启动子活性。MORC2过表达导致NDRG1启动子的H3Ac和H4Ac降低。重要的是，我们发现NDRG1在MORC2介导的CRC细胞迁移和侵袭的体外促进以及CRC细胞在体内的肺转移中至关重要。此外，在结直肠癌患者中，MORC2表达与NDRG1表达呈负相关。在结肠癌患者中，MORC2高表达与淋巴结转移（P = 0.019）和pTNM分期差（P = 0.02）显著相关，MORC2表达与预后差相关。因此，我们的研究结果有助于了解MORC2下调NDRG1的调控机制，并建议MORC2作为CRC的潜在治疗靶点。
MORC2 (microrchidia family CW‐type zinc finger 2) is a newly identified chromatin remodeling protein that functions in diverse biological processes including gene transcription. NDRG1 is a metastasis suppressor and a prognostic biomarker for colorectal cancer (CRC). However, the relationship between MORC2 and NDRG1 transcriptional regulation and the roles of MORC2 in CRC remain elusive. Here, we showed that MORC2 downregulated NDRG1 mRNA, protein levels, and promoter activity in CRC cells. We also found that MORC2 bound to the −446 to −213 bp region of the NDRG1 promoter. Mechanistically, histone deacetylase sirtuin 1 (SIRT1) was involved in NDRG1 transcriptional regulation. MORC2 was able to interact with SIRT1 and inhibit NDRG1 promoter activity cumulatively with SIRT1. MORC2 overexpression led to a decrease of H3Ac and H4Ac of the NDRG1 promoter. Importantly, we showed that NDRG1 was essential in MORC2‐mediated promotion of CRC cell migration and invasion in vitro, as well as lung metastasis of CRC cells in vivo. Moreover, MORC2 expression correlated negatively with NDRG1 expression in CRC patients. High expression of MORC2 was significantly associated with lymph node metastasis (P = 0.019) and poor pTNM stage (P = 0.02) and the expression of MORC2 correlated with poor prognosis in colon cancer patients. Our findings thus contribute to the knowledge of the regulatory mechanism of MORC2 in downregulating NDRG1, and suggest MORC2 as a potential therapeutic target for CRC.
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