Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms

Douse, Christopher H.; Bloor, Stuart; Liu, Yangci; Shamin, Maria; Tchasovnikarova, Iva A.; Timms, Richard T.; Lehner, Paul J.; Modis, Yorgo

doi:10.1038/s41467-018-03045-x

Cited by 74 publications

(88 citation statements)

References 50 publications

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“…In support of our findings, a recent study on crystal structure of MORC2 suggests that the M276I mutation would cause a conformational change that may affect its interaction with other proteins. In addition, this mutation would not be expected to substantially alter the stability or half-life of MORC2 (47).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with a high propensity for distant metastasis and limited treatment options, yet its molecular underpinnings remain largely unknown. Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein whose mutations have been causally implicated in several neurologic disorders. Here, we report that a cancer-associated substitution of methionine to isoleucine at residue 276 (M276I) of MORC2 confers gain-of-function properties in the metastatic progression of TNBC. Expression of mutant MORC2 in TNBC cells increased cell migration, invasion, and lung metastasis without affecting cell proliferation and primary tumor growth compared with its wild-type counterpart. The M276I mutation enhanced binding of MORC2 to heterogeneous nuclear ribonucleoprotein M (hnRNPM), a component of the spliceosome machinery. This interaction promoted an hnRNPM-mediated splicing switch of CD44 from the epithelial isoform (CD44v) to the mesenchymal isoform (CD44s), ultimately driving epithelial-mesenchymal transition (EMT). Knockdown of hnRNPM reduced the binding of mutant MORC2 to CD44 pre-mRNA and reversed the mutant MORC2-induced CD44 splicing switch and EMT, consequently impairing the migratory, invasive, and lung metastatic potential of mutant MORC2-expressing cells. Collectively, these findings provide the first functional evidence for the M276I mutation in promoting TNBC progression. They also establish the first mechanistic connection between MORC2 and RNA splicing and highlight the importance of deciphering unique patient-derived mutations for optimizing clinical outcomes of this highly heterogeneous disease. A gain-of-function effect of a single mutation on MORC2 promotes metastasis of triple-negative breast cancer by regulating CD44 splicing. .

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…MORC2 interacts with the HUSH complex and MORC2 enrichment at HUSH targets is dependent on the HUSH complex [117]. The MORC2 ATPase module dimerizes upon ATP binding and MORC2 binds both free dsDNA and nucleosomal DNA [118]. MORC2 might be recruited by the HUSH complex to chromatin, where dimerization of two DNA-bound MORC2 can promote DNA loop formation and chromatin compaction [118].…”

Section: Retroelement-type Specific Regulationmentioning

confidence: 99%

SETDB1-Mediated Silencing of Retroelements

Fukuda

Shinkai

2020

Viruses

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SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) is a protein lysine methyltransferase and methylates histone H3 at lysine 9 (H3K9). Among other H3K9 methyltransferases, SETDB1 and SETDB1-mediated H3K9 trimethylation (H3K9me3) play pivotal roles for silencing of endogenous and exogenous retroelements, thus contributing to genome stability against retroelement transposition. Furthermore, SETDB1 is highly upregulated in various tumor cells. In this article, we describe recent advances about how SETDB1 activity is regulated, how SETDB1 represses various types of retroelements such as L1 and class I, II, and III endogenous retroviruses (ERVs) in concert with other epigenetic factors such as KAP1 and the HUSH complex and how SETDB1-mediated H3K9 methylation can be maintained during replication.

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“…MORC2 is a poorly characterized, highly conserved protein with known nuclear localization [35]. Based on studies of MORC homologs in prokaryotes, MORC2 is predicted to play a role in chromatin remodeling in eukaryotic cells, although its exact function remains to be assessed [17,36].…”

Section: Discussionmentioning

confidence: 99%

MORC2 Enhances Tumor Growth by Promoting Angiogenesis and Tumor-Associated Macrophage Recruitment via Wnt/β-Catenin in Lung Cancer

Liu

Sun

2018

Cell Physiol Biochem

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Background/Aims: In this study, we aimed to investigate how MORC family CW-type zinc finger 2 (MORC2) affects tumor progression of lung cancer. Methods: The MORC2 level was analyzed by real-time RT-PCR and immunohistochemistry (IHC) in normal control tissues and lung cancers. LL/2 cells overexpressing MORC2 were used to study how MORC2 expression influences lung cancer progression. The effects of MORC2 on cell viability, migration and invasion were assessed by MTT assay, Western blotting, and transwell assays, respectively. Afterwards, the effects of MORC2 on the activation of the Wnt/β-catenin pathway were explored by Western blotting. The effects of MORC2 on tumor-associated macrophages (TAM) were determined by immunofluorescence (IF) staining, real-time RT-PCR and Western blotting. Results: Our results showed that MORC2 was upregulated in lung cancers relative to adjacent tissues. The results also demonstrated that MORC2 promoted lung cancer tumor growth in vivo. Additionally, MORC2 overexpression stimulated the upregulation of vascular endothelial growth factor (VEGF), driving angiogenesis. MORC2 overexpression in LL/2 also increased the amount of aldehyde dehydrogenase-1 (ALDH1) protein, indicating that MORC2 increased cancer stem cell features. We further determined that MORC2 activated Wnt/β-catenin signaling in lung cancer cells. Upregulation of macrophage-recruiting genes including VEGF and Macrophage-specific colony stimulating factor (CSF-1) recruits TAMs to the tumor site, which has the net effect of promoting additional tumor growth and metastasis. Conclusion: Our data suggest that MORC2 overexpression can drive lung cancer growth by stimulating the recruitment of TAMs in addition to angiogenesis and that activation of Wnt/β-signaling may be a key pathway underlying this phenotype that is amenable to pharmacological intervention.

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Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms

Cited by 74 publications

References 50 publications

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

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

SETDB1-Mediated Silencing of Retroelements

MORC2 Enhances Tumor Growth by Promoting Angiogenesis and Tumor-Associated Macrophage Recruitment via Wnt/β-Catenin in Lung Cancer

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