Microrchidia 2/histone deacetylase 1 complex regulates E-cadherin gene expression and function.

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.

Novel Insights into the Role of Chromatin Remodeler MORC2 in Cancer.

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.

MORC2 and MAX contributes to the expression of glycolytic enzymes, breast cancer cell proliferation and migration.

Cancer cell proliferation is a high energy demanding process, where the cancer cells acquire energy by high rates of glycolysis, and this phenomenon is known as the "Warburg effect". Microrchidia 2 (MORC2), an emerging chromatin remodeler, is over expressed in several cancers including breast cancer and found to promote cancer cell proliferation. However, the role of MORC2 in glucose metabolism in cancer cells remains unexplored. In this study, we report that MORC2 interacts indirectly with the genes involved in glucose metabolism via transcription factors MAX (MYC-associated factor X) and MYC. We also found that MORC2 co-localizes and interacts with MAX. Further, we observed a positive correlation of expression of MORC2 with glycolytic enzymes Hexokinase 1 (HK1), Lactate dehydrogenase A (LDHA) and Phosphofructokinase platelet (PFKP) type in multiple cancers. Surprisingly, the knockdown of either MORC2 or MAX not only decreased the expression of glycolytic enzymes but also inhibited breast cancer cell proliferation and migration. Together, these results demonstrate the involvement of the MORC2/MAX signaling axis in the expression of glycolytic enzymes and breast cancer cell proliferation and migration.

Metastasis-associated protein 1: A potential driver and regulator of the hallmarks of cancer.

Metastasis-associated protein 1 (MTA1) is an emerging transcriptional co-regulator and was found to be aberrantly expressed in different types of cancers. MTA1 has been reported to regulate multiple cancer-related signalling pathways leading to tumour progression and metastasis. Recently, MTA1 was also implicated in cancer metabolism, where it was found to regulate the 'Warburg effect' to drive breast cancer cell invasion. Overall, the functional dynamism of MTA1 can be attributed to its dual co-regulatory effects in regulating a diverse array of target genes involved in cell proliferation, DNA damage repair, angiogenesis, invasion, migration, metastasis, and metabolism in different types of cancers. In this review, we have attempted to provide a brief summary of MTA1 as a modulator of the hallmarks of cancer.

Zinc transporter LIV1: A promising cell surface target for triple negative breast cancer.

Breast cancer is one of the leading causes contributing to the global cancer burden. The triple negative breast cancer (TNBC) molecular subtype accounts for the most aggressive type. Despite progression in therapeutic options and prognosis in breast cancer treatment options, there remains a high rate of distant relapse. With advancements in understanding the role of zinc and zinc carriers in the prognosis and treatment of the disease, the scope of precision treatment/targeted therapy has been expanded. Zinc levels and zinc transporters play a vital role in maintaining cellular homeostasis, tumor surveillance, apoptosis, and immune function. This review focuses on the zinc transporter, LIV1, as an essential target for breast cancer prognosis and emerging treatment options. Previous studies give an insight into the role of LIV1 in fulfilling the most important hallmarks of cancer such as apoptosis, metastasis, invasion, and evading the immune system. Normal tissue expression of LIV1 is limited. Higher expression of LIV1 has been linked to Epithelial-Mesenchymal Transition, histological grade of cancer, and early node metastasis. LIV1 was found to be one of the attractive targets in the therapeutic hunt for TNBCs. TNBCs are an immunogenic breast cancer subtype. As zinc transporters are known to serve as the metabolic gatekeepers of immune cells, this review bridges tumor infiltrating lymphocytes, TNBC and LIV1. In addition, the suitability of LIV1 as an antibody-drug conjugate (Seattle genetics [SGN]-LIV1A) target in TNBC, represents a promising strategy for patients. Early clinical trial results reveal that this novel agent reduces tumor burden by inducing mitotic arrest, immunomodulation, and immunogenic cell death, warranting further investigation of SGN-LIV1A in combination with immuno-oncology agents. Priming the patient's immune response in combination with SGN-LIV1A could eventually change the landscape for the TNBC patient population.

Structural and Functional Attributes of Microrchidia Family of Chromatin Remodelers.

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.

MORC2/ß-catenin signaling axis promotes proliferation and migration of breast cancer cells.

Although Microrchidia 2 (MORC2) is overexpressed in many types of human cancer, its role in breast cancer progression remains unknown. Here, we report that the chromatin remodeler MORC2 expression positively correlates with ß-catenin expression in breast cancer cell lines and patients. Overexpression of MORC2 augmented the expression of ß-catenin and its target genes, cyclin D1 and c-Myc. Consistent with these results, we found MORC2 knockdown resulted in decreased expression of ß-catenin and its target genes. Surprisingly, we observed that c-Myc, the target gene of ß-catenin, regulated the MORC2-ß-catenin signaling axis through a feedback mechanism. We demonstrated that MORC2 regulates ß-catenin expression and function by modulating the phosphorylation of AKT. In addition, we observed reduced proliferation and migration of MORC2 overexpressing breast cancer cells upon ß-catenin inhibition. Overall, our results demonstrate that MORC2 promotes breast cancer cell proliferation and migration by regulating ß-catenin signaling.

Virtual screening of curcumin and its analogs against the spike surface glycoprotein of SARS-CoV-2 and SARS-CoV.

COVID-19, a new pandemic caused by SARS-CoV-2, was first identified in 2019 in Wuhan, China. The novel corona virus SARS-CoV-2 and the 2002 SARS-CoV have 74% identity and use similar mechanisms to gain entry into the cell. Both the viruses enter the host cell by binding of the viral spike glycoprotein to the host receptor, angiotensin converting enzyme 2 (ACE2). Targeting entry of the virus has a better advantage than inhibiting the later stages of the viral life cycle. The crystal structure of the SARS-CoV (6CRV: full length S protein) and SARS-CoV-2 Spike proteins (6M0J: Receptor binding domain, RBD) was used to determine potential small molecule inhibitors. Curcumin, a naturally occurring phytochemical in Curcuma longa, is known to have broad pharmacological properties. In the present study, curcumin and its derivatives were docked, using Autodock 4.2, onto the 6CRV and 6M0J to study their capability to act as inhibitors of the spike protein and thereby, viral entry. The curcumin and its derivatives displayed binding energies, ΔG, ranging from -10.98 to -5.12 kcal/mol (6CRV) and -10.01 to -5.33 kcal/mol (6M0J). The least binding energy was seen in bis-demethoxycurcumin with: ΔG = -10.98 kcal/mol (6CRV) and -10.01 kcal/mol (6M0J). A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin and few of its derivatives as SARS-CoV-2 spike protein inhibitors. However, further research is necessary to investigate the ability of these compounds as viral entry inhibitors.Communicated by Ramaswamy H. Sarma.

MORC2 Interactome: Its Involvement in Metabolism and Cancer.

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.

The chromatin modifier MORC2 affects glucose metabolism by regulating the expression of lactate dehydrogenase A through a feed forward loop with c-Myc.

Microrchidia family CW-type zinc finger 2 (MORC2) is a recently identified chromatin modifier with an emerging role in cancer metastasis. However, its role in glucose metabolism, a hallmark of malignancy, remains to be explored. We found that MORC2 is a glucose-inducible gene and a target of c-Myc. Our meta-analysis revealed that MORC2 expression is positively correlated with the expression of enzymes involved in glucose metabolism in breast cancer patients. Furthermore, overexpression of MORC2 in MCF-7 and BT-549 cells augmented the expression and activity of a key glucose metabolism enzyme, lactate dehydrogenase A (LDHA). Conversely, selective knockdown of MORC2 by siRNA markedly decreased LDHA expression and activity and in turn reduced cancer cell migration. Collectively, these findings provide evidence that MORC2, a glucose-inducible gene, modulates the migration of breast cancer cells through the MORC2-c-Myc-LDHA axis.

MTA1 coregulator regulates LDHA expression and function in breast cancer.

Metastasis Associated Protein1 (MTA1) is a chromatin modifier and its expression is significantly associated with prognosis of many cancers. However, its role in glucose metabolism remains unexplored. Here, we report that MTA1 has a significant role in glucose metabolism where MTA1 regulates the LDHA expression and activity and subsequently its function in breast cancer motility. The results showed that MTA1 expression is positively correlated with the LDHA expression levels in breast cancer patients. Further, it was found that MTA1 is necessary for the optimal expression of LDHA. The underlying molecular mechanism involves the interaction of MTA1 with c-Myc and recruitment of MTA1-c-Myc complex on to the LDHA promoter to regulate its transcription. Consequently, the LDHA knock down using LDHA specific siRNA in MCF7 cells stably expressing MTA1 reduced the migration of MCF7 cells. Altogether these findings revealed the regulatory role for MTA1 in LDHA expression and its resulting biological function.

Combined drug therapeutic strategies for the effective treatment of Triple Negative Breast Cancer.

TNBC (Triple Negative Breast Cancer) is a subtype of breast cancer with an aggressive phenotype which shows high metastatic capability and poor prognosis. Owing to its intrinsic properties like heterogeneity, lack of hormonal receptors and aggressive phenotype leave chemotherapy as a mainstay for the treatment of TNBC. Various studies have demonstrated that chemotherapy alone or therapeutic drugs targeting TNBC pathways, epigenetic mechanisms and immunotherapy alone have not shown significant improvement in TNBC patients. On the other hand, a combination of therapeutic drugs or addition of chemotherapy with therapeutic drugs has shown substantial improvement in results and proven to be an effective strategy for TNBC treatment. This review sheds light on effective combinational drug strategies and current clinical trial status of various combinatorial drugs for the treatment of TNBC.

Metastasis-associated protein 1 is an integral component of the circadian molecular machinery.

The mammalian circadian clock regulates the daily cycles of many important physiological processes, but its mechanism is not well understood. Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. Knockout of MTA1 in mice disrupts the free-running period of circadian rhythms under constant light and normal entrainment of behaviour to 12-h-light/12-h-dark cycles. The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. Moreover, MTA1 deacetylates BMAL1 at lysine 538 through regulating deacetylase SIRT1 expression, thus disturbing the CRY1-mediated negative feedback loop. These findings uncover a previously unappreciated role for MTA1 in maintenance of circadian rhythmicity through acting on the positive limb of the clock machinery.

MTA1 promotes STAT3 transcription and pulmonary metastasis in breast cancer.

Overexpression of the prometastatic chromatin modifier protein metastasis tumor antigen 1 (MTA1) in human cancer contributes to tumor aggressiveness, but the role of endogenous MTA1 in cancer has not been explored. Here, we report the effects of selective genetic depletion of MTA1 in a physiologically relevant spontaneous mouse model of breast cancer pulmonary metastasis. We found that MTA1 acts as a mandatory modifier of breast-to-lung metastasis without effects on primary tumor formation. The underlying mechanism involved MTA1-dependent stimulation of STAT3 transcription through action on the MTA1/STAT3/Pol II coactivator complex, and, in turn, on the expression and functions of STAT3 target genes including Twist1. Accordingly, we documented a positive correlation between levels of MTA1 and STAT3 in publicly available breast cancer data sets. Together, our findings reveal an essential modifying role of the physiologic level of MTA1 in supporting pulmonary metastasis of breast cancer.

MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response.

Chromatin dynamics play a central role in maintaining genome integrity, but how this is achieved remains largely unknown. Here, we report that microrchidia CW-type zinc finger 2 (MORC2), an uncharacterized protein with a derived PHD finger domain and a conserved GHKL-type ATPase module, is a physiological substrate of p21-activated kinase 1 (PAK1), an important integrator of extracellular signals and nuclear processes. Following DNA damage, MORC2 is phosphorylated on serine 739 in a PAK1-dependent manner, and phosphorylated MORC2 regulates its DNA-dependent ATPase activity to facilitate chromatin remodeling. Moreover, MORC2 associates with chromatin and promotes gamma-H2AX induction in a PAK1 phosphorylation-dependent manner. Consequently, cells expressing MORC2-S739A mutation displayed a reduction in DNA repair efficiency and were hypersensitive to DNA-damaging agent. These findings suggest that the PAK1-MORC2 axis is critical for orchestrating the interplay between chromatin dynamics and the maintenance of genomic integrity through sequentially integrating multiple essential enzymatic processes.