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

Abstract

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.

Differences and overlap in plasma protein expression during colorectal cancer progression

“…In CRC, MORC2 has been shown to inhibit N-myc downstream regulated gene 1 (NDRG1), a metastasis suppressor, which promotes cell migration, invasion, and lung metastasis. This study also showed that MORC2 was upregulated in CRC tissues, and high expression was found to be associated with lymph node metastasis [30]. We found that MORC2 levels are higher in plasma samples from patients with lymph node positive CRC, and the findings of these studies together indicate that MORC2 is of interest as a new biomarker, although further studies are needed to elucidate its role in CRC.…”

Potential Biomarkers of Colon Adenocarcinoma Based on Weighted Gene Co-Expression Network Analysis

“…Targeting E2F3 can inhibit the proliferation and induce the apoptosis of colorectal cancer cells and induce the expression of E2F3 to promote the proliferation of colorectal cancer cells [35][36][37][38]. MORC2 is also considered a candidate gene for colon cancer, and previous studies have shown that MORC2 promotes the development of invasive colorectal cancer phenotypes by inhibiting NDRG1 [39][40].…”

Microrchidia family CW‑type zinc finger 2 promotes the proliferation, invasion, migration and epithelial‑mesenchymal transition of glioma by regulating PTEN/PI3K/AKT signaling via binding to N‑myc downstream regulated gene 1 promoter

“…A study has demonstrated that MORC2 expression is notably enhanced in glioma tissues compared with the adjacent tissues, and the higher the level of glioma differentiation, the higher the expression of MORC2 is ( 6 ). Additionally, MORC2 was found to promote the proliferation, invasion and migration of colorectal cancer cells by binding with the promoter region of N-myc downstream regulated gene 1 (NDRG1), a well-characterized metastasis suppressor that has been demonstrated to have the potential to be developed as a target for antimetastatic therapy ( 7 , 8 ). In human cholangiocarcinoma, MORC2 is reported to accelerate the growth and metastasis of cholangiocarcinoma cells via activation of PI3K/Akt signaling ( 9 ).…”