MORC2 promotes development of an aggressive colorectal cancer phenotype through inhibition of NDRG1

Summary

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 down‐regulated NDRG1 mRNA, protein levels and promoter activity in CRC cells. We also found that MORC2 bound to the –446~–213bp region of the NDRG1 promoter. Mechanistically, histone deacetylase 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 decreasement of H3Ac and H4Ac of the NDRG1 promoter. Importantly, we demonstrated 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 down‐regulating NDRG1, and suggest MORC2 as a potential therapeutic target for CRC.

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