Cancer-Associated MORC2-Mutant M276I Regulates an hnRNPM-Mediated CD44 Splicing Switch to Promote Invasion and Metastasis in Triple-Negative Breast Cancer

Zhang, Fang Lin; Cao, Jin; Xie, Haiyang; Sun, Rui; Li, Yang; Shao, Zhi Ming; Li, Da Qiang

doi:10.1158/0008-5472.can-17-1394

Cited by 83 publications

(96 citation statements)

References 49 publications

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“…It is reported that MORC2 promoted breast cancer invasion and metastasis through a PRD domain‐mediated interaction with catenin delta 1 . Recently, it has been shown that MORC2‐mutant M276I promotes metastasis of triple‐negative breast cancer by regulating CD44 splicing . Moreover, MORC2 promotes cancer stemness and tumorigenesis by facilitating DNA methylation‐dependent silencing of Hippo signaling in hepatocellular carcinoma .…”

Section: Introductionmentioning

confidence: 99%

“…12 Recently, it has been shown that MORC2-mutant M276I promotes metastasis of triple-negative breast cancer by regulating CD44 splicing. 13 Moreover, MORC2 promotes cancer stemness and tumorigenesis by facilitating DNA methylation-dependent silencing of Hippo signaling in hepatocellular carcinoma. 14 Additionally, MORC2 was found to be one of the mutation hotspot oncogenes in CRCs with microsatellite instability.…”

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confidence: 99%

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

Liu

Shao

et al. 2018

Cancer Science

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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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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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

Liu

Shao

et al. 2018

Cancer Science

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“…Secondary Abs for immunoblotting and immunofluorescence were from Cell Signaling Technology. Immunoblotting, IP, and immunofluorescence have previously been described . Briefly, for immunoblotting analyses, cells were lysed in modified RIPA buffer (50 mmol/L Tris‐HCl, pH 7.4, 150 mmol/L NaCl, 1% NP‐40, 0.25% sodium deoxycholate, 0.1% SDS, and 1 mmol/L EDTA) containing 1× protease inhibitor cocktail and 1× phosphatase inhibitor cocktail (Bimake, Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting, IP, and immunofluorescence have previously been described. 27,30 Briefly, for immunoblotting analyses, cells were lysed in modified RIPA buffer (50 mmol/L Tris-HCl, pH 7.4, 150 mmol/L NaCl, 1% NP-40, 0.25% sodium deoxycholate, 0.1% SDS, and 1 mmol/L EDTA) containing 1× protease inhibitor cocktail and 1× phosphatase inhibitor cocktail (Bimake, Shanghai, China). Proteins were quantified using the bicinchoninic acid assay (Yeasen, Shanghai, China), resolved by SDS-PAGE, and transferred onto PVDF membrane (Millipore, Billerica, MA, USA).…”

Section: Antibodies Immunoblotting Immunoprecipitation and Immunmentioning

confidence: 99%

Deubiquitinase ubiquitin‐specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells

Shao

et al. 2019

Cancer Science

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The E3 ubiquitin ligase ring finger protein 115 ( RNF 115) is overexpressed in more than half of human breast tumors and is implicated in the pathogenesis and progression of breast cancer. However, the mechanism behind RNF 115 overexpression in breast tumors remains largely unknown. Here we report that ubiquitin‐specific protease 9X ( USP 9X), a substrate‐specific deubiquitinating enzyme, stabilizes RNF 115 and thereby regulates its biological functions in breast cancer cells. Immunoprecipitation and GST pull‐down assays showed that USP 9X interacted with RNF 115. Depletion of RNF 115 by si RNA s or overexpression of RNF 115 did not significantly affect USP 9X expression. In contrast, knockdown of USP 9X in breast cancer cells by si RNA s reduced RNF 115 protein abundance, which was partially restored following treatment with proteasome inhibitor MG ‐132. Moreover, depletion of USP 9X reduced the half‐life of RNF 115 and increased its ubiquitination. Conversely, overexpression of USP 9X resulted in an accumulation of RNF 115 protein, accompanied by a decrease in its ubiquitination. RNF 115 mRNA levels were unaffected by overexpression or knockdown of USP 9X. Furthermore, USP 9X protein expression levels correlated positively with RNF 115 in breast cancer cell lines and breast tumor samples. Importantly, reintroduction of RNF 115 in USP 9X‐depleted cells partially rescued the reduced proliferation, migration, and invasion of breast cancer cells by USP 9X knockdown. Collectively, these findings indicate that USP 9X is a stabilizer of RNF 115 protein and that the USP 9X‐ RNF 115 signaling axis is implicated in the breast cancer malignant phenotype.

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“…Immunoblotting analysis, immunoprecipitation assays, and immunofluorescent staining were performed as described previously in details. [39][40][41]…”

Section: Antibodies Immunoblotting Immunoprecipitation Assays Anmentioning

confidence: 99%

USP9X stabilizes BRCA1 and confers resistance to DNA‐damaging agents in human cancer cells

Zhang

et al. 2019

Cancer Medicine

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BRCA1, a multifunctional protein with an important role in DNA double‐strand break repair by homologous recombination (HR), is subjected to ubiquitin‐dependent degradation. To date, several E3 ubiquitin ligases have been identified to govern BRCA1 stability, but the deubiquitinase that counteracts its turnover remains undefined. In this study, we report that the ubiquitin‐specific protease 9X (USP9X) is a bona fide deubiquitinase for BRCA1 in human cancer cells. Reciprocal immunoprecipitation assays demonstrated that USP9X interacted with BRCA1. Depletion of USP9X by short interfering RNAs or inhibition of USP9X by the small‐molecular inhibitor WP1130 significantly reduced BRCA1 protein abundance, without affecting its mRNA levels. In contrast, overexpression of wild‐type USP9X, but not its deubiquitinase activity‐defective mutant (C1566S), resulted in an upregulation of BRCA1 protein levels. Moreover, USP9X depletion reduced the half‐life of BRCA1, accompanied by an increase in its ubiquitination. HR assays showed that knockdown of USP9X significantly reduced HR efficiency, which was partially rescued by reintroduction of BRCA1 into USP9X‐depleted cells. In support of these findings, USP9X knockdown significantly enhanced sensitivity to PARP inhibitor Olaparib and methyl methanesulfonate (MMS). Collectively, these results establish USP9X as a deubiquitinase for BRCA1 and reveal a previously unrecognized role of USP9X in the regulation of HR repair and the sensitivity of cancer cells to DNA‐damaging agents.

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Cancer-Associated MORC2-Mutant M276I Regulates an hnRNPM-Mediated CD44 Splicing Switch to Promote Invasion and Metastasis in Triple-Negative Breast Cancer

Cited by 83 publications

References 49 publications

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

Deubiquitinase ubiquitin‐specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells

USP9X stabilizes BRCA1 and confers resistance to DNA‐damaging agents in human cancer cells

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