RESUMO
A newly discovered chromatin remodeler, MORC2, is a Microrchidia (MORC) family member. MORC2 acts as a chromatin remodeler by binding to the DNA and changing chromatin conformation using its ATPase domain. MORC2 is highly expressed in a variety of human cancers. It controls diverse signaling pathways essential for cancer development through its target genes and interacting partners. MORC2 promotes cancer cells' growth, invasion, and migration by regulating the expression of genes involved in these processes. MORC2 is localized primarily in the nucleus and is also found in the cytoplasm. In the cytoplasm, MORC2 interacts with adenosine triphosphate (ATP)-citrate lyase (ACLY) to promote lipogenesis and cholesterogenesis in cancer. In the nucleus, MORC2 interacts with the transcription factor c-Myc to control the transcription of genes involved in glucose metabolism to drive cancer cell migration and invasion. Furthermore, MORC2 recruits on to the promoters of tumor suppressor genes to repress their transcription and expression to promote oncogenesis. In addition to its crucial function in oncogenesis, it plays a vital role in DNA repair. Overall, this review concisely summarizes the current knowledge about MORC2-regulated molecular pathways involved in cancer.
Assuntos
Cromatina , Neoplasias , Humanos , Cromatina/genética , Fatores de Transcrição/metabolismo , Neoplasias/genética , Reparo do DNA , CarcinogêneseRESUMO
Although Microrchidia 2 (MORC2) is widely overexpressed in human malignancies and linked to cancer cell proliferation, metabolism, and metastasis, the mechanism of action of MORC2 in cancer cell migration and invasion is yet undeciphered. Here, we identified for the first time that MORC2, a chromatin remodeler, regulates E-cadherin expression and, subsequently regulates breast cancer cell migration and invasion. We observed a negative correlation between the expression levels of MORC2 and E-cadherin in breast cancer. Furthermore, the overexpression of MORC2 resulted in decreased expression levels of E-cadherin. In addition, co-immunoprecipitation and chromatin immunoprecipitation assays revealed that MORC2 interacts with HDAC1 and gets recruited onto the E-cadherin promoter to inhibit its transcription, thereby suppress its expression. Consequently, knockdown of HDAC1 in MORC2-overexpressing cells led to reduced cancer cell migration and invasion. Interestingly, we noticed that MORC2-regulated glucose metabolism via c-Myc, and LDHA, also modulates the expression of E-cadherin. Collectively, these results demonstrate for the first time a mechanistic role for MORC2 as an upstream regulator of E-cadherin expression and its associated functions in breast cancer.
Assuntos
Neoplasias da Mama , Histona Desacetilase 1 , Humanos , Feminino , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Linhagem Celular Tumoral , Caderinas/genética , Caderinas/metabolismo , Neoplasias da Mama/genética , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/metabolismoRESUMO
Chromatin remodelers affect the spatio-temporal dynamics of global gene-expression by structurally modulating and/or reorganizing the chromatin. Microrchidia (MORC) family is a relatively new addition to the four well studied families of chromatin remodeling proteins. In this review, we discuss the current understanding of the structural aspects of human MORCs as well as their epigenetic functions. From a molecular and systems-level perspective, we explore their participation in phase-separated structures, possible influence on various biological processes through protein-protein interactions, and potential extra-nuclear roles. We describe how dysregulation/dysfunction of MORCs can lead to various pathological conditions. We conclude by emphasizing the importance of undertaking integrated efforts to obtain a holistic understanding of the various biological roles of MORCs.
Assuntos
Montagem e Desmontagem da Cromatina , Cromatina , Epigênese Genética , Proteínas Nucleares , Núcleo Celular/metabolismo , Cromatina/química , Humanos , Proteínas Nucleares/química , Conformação ProteicaRESUMO
Microrchidia 2 (MORC2) is an emerging chromatin modifier with a role in chromatin remodeling and epigenetic regulation. MORC2 is found to be upregulated in most cancers, playing a significant role in tumorigenesis and tumor metastasis. Recent studies have demonstrated that MORC2 is a scaffolding protein, which interacts with the proteins involved in DNA repair, chromatin remodeling, lipogenesis, and glucose metabolism. In this review, we discuss the domain architecture and cellular and subcellular localization of MORC2. Further, we highlight MORC2-specific interacting partners involved in metabolic reprogramming and other pathological functions such as cancer progression and metastasis.