ATP-dependent NuRD repressor complexes involve combinatorial assembly of its subunits. However, the mechanism of gene transcription by MTA1/NuRD remains enigmatic. Here we report that MTA1 ...methylation by G9a methytransferase and demethylation by LSD1 determines the nucleosome remodeling and transcriptional outcome. Contrary to the current static repressor model of the NuRD complex, we discovered that MTA1 association with nucleosomes and corepressor/coactivator complexes is dynamic. While methylated MTA1 is required for the NuRD repressor complex, demethylated MTA1 recognizes the bivalent histone H3K4-AcK9 mark and recruits coactivator NURF-trithorax remodeling complex in a signaling-dependent manner. MTA1’s lysine 532 methylation represents a molecular switch as methylated and demethylated MTA1 nucleate NuRD or NURF complexes with opposite functions in a cyclical manner. In addition, MTA1 possesses an inherent histone amplifier activity with an instructive role in impacting the epigenetic landscape, providing a new perspective to the molecular governance of dual coregulator functions of a master coregulator.
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► MTA1 methylation dictates the chromatin remodeling activity of the NuRD complex ► MTA1 interprets the “nucleosome code” via engaging multivalent chromatin marks ► Methylated and demethylated MTA1 nucleate complexes with opposite functions ► MTA1’s methylation status plays an instructive role in the transcriptional outcome
Cancer cells are remarkably adaptive to diverse survival strategies, probably due to its ability to interpret signaling cues differently than the normal cells. It appears as if cancer cells are ...constantly sampling, selecting and adapting signaling pathways to favor its proliferation. This process of successful adaptive evolution eventually renders a retractile nature to therapeutic regimens, fueling to the process of cancer progression. Based on plethora of available information, it is now evident that multiple signaling pathways eventually converge, perhaps, in a tempo-spatial manner, onto DNA template-dependent dynamic processes. Considering the complexity and packaging of eukaryotic genome, this process involves energy-dependent sub-events mediated by chromatin remodelers. Chromatin remodeler proteins function as gatekeepers and constitute a major determinant of accessibility of accessory factors to nucleosome DNA, allowing a wide repertoire of biological functions. And thus, aberrant expression or epigenetic modulation of remodeler proteins confers a unique ability to cancer cells to reprogram its genome for the maintenance of oncogenic phenotypes. Cancer cells can uniquely select a multi-subunit remodeler proteome for oncogenic advantage. This review summarizes our current understanding and importance of remodeler and chromatin proteins in cancer biology and also highlights the paradoxical role of proteins with or without dual-regulator functions. It is our hope that an in-depth understanding of these events is likely to provide a next set of opportunities for novel strategies for targeted cancer therapeutics.
Bladder cancer has been successfully treated with immunotherapy, whereas prostate cancer is a cold tumor with inadequate immune-related treatment response. A greater understanding of the tumor ...microenvironment and methods for harnessing the immune system to address tumor growth will be needed to improve immunotherapies for both prostate and bladder cancer. Here, we provide an overview of prostate and bladder cancer, including fundamental aspects of the disease and treatment, the elaborate cellular makeup of the tumor microenvironment, and methods for exploiting relevant pathways to develop more effective treatments.
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.
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► MORC2 is a DNA damage-responsive phosphoprotein activated by PAK1 kinase ► MORC2 regulates phosphorylation-coupled, ATPase-dependent chromatin remodeling ► MORC2 facilitates gamma-H2AX induction independently of PIKK kinases ► MORC2 promotes DSB repair in a PAK1 phosphorylation-dependent manner
Chromatin dynamics play a critical role in maintaining genome integrity. Li, Kumar, and colleagues demonstrate that microrchidia CW-type zinc finger 2 (MORC2) is a chromatin remodeling protein and a modifier of radiosensitivity. MORC2 facilitates ATPase-coupled chromatin relaxation to govern DNA double-strand break signaling in a p21-activated kinase 1 (PAK1) phosphorylation-dependent manner. These findings establish that the PAK1-MORC2 axis is emerging as a central mediator of the cellular response to DNA damage through sequentially integrating multiple essential enzymatic processes.
The androgen receptor (AR) plays a central role in establishing an oncogenic cascade that drives prostate cancer progression. Some prostate cancers escape androgen dependence and are often associated ...with an aggressive phenotype. The oestrogen receptor alpha (ERα) is expressed in prostate cancers, independent of AR status. However, the role of ERα remains elusive. Using a combination of chromatin immunoprecipitation (ChIP) and RNA-sequencing data, we identified an ERα-specific non-coding transcriptome signature. Among putatively ERα-regulated intergenic long non-coding RNAs (lncRNAs), we identified nuclear enriched abundant transcript 1 (NEAT1) as the most significantly overexpressed lncRNA in prostate cancer. Analysis of two large clinical cohorts also revealed that NEAT1 expression is associated with prostate cancer progression. Prostate cancer cells expressing high levels of NEAT1 were recalcitrant to androgen or AR antagonists. Finally, we provide evidence that NEAT1 drives oncogenic growth by altering the epigenetic landscape of target gene promoters to favour transcription.
The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and ...elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.
Cancer cells frequently exhibit deregulation of coregulatory molecules to drive the process of growth and metastasis. One such group of ubiquitously expressed coregulators is the ...metastasis-associated protein (MTA) family, a critical component of the nucleosome remodeling and histone deacetylase (NuRD) complex. MTA1 occupies a special place in cancer biology because of its dual corepressor or coactivator nature and widespread overexpression in human cancers. Here, we highlight recent advances in our understanding of the vital roles of MTA1 on transformation, epithelial-mesenchymal transition, and the functions of key cancer-relevant molecules such as a nexus of multiple oncogenes and tumor suppressors. In addition to its paramount role in oncogenesis, we reveal several new physiologic functions of MTA1 related to DNA damage, inflammatory responses, and infection, in which MTA1 functions as a permissive "gate keeper" for cancer-causing parasites. Further, these discoveries unraveled the versatile multidimensional modes of action of MTA1, which are independent of the NuRD complex and/or transcription. Given the emerging roles of MTA1 in DNA repair, inflammation, and parasitism, we discuss the possibility of MTA1-targeted therapy for use not only in combating cancer but also in other inflammation and pathogen-driven pathologic conditions.
Diffusing alpha-emitters radiation therapy (DaRT) is the only known method for treating solid tumors with highly destructive alpha radiation. More importantly, as a monotherapy, DaRT has been shown ...to induce a systemic antitumor immune response following tumor ablation. Here, immunomodulatory strategies to boost the antitumor immune response induced by DaRT, and the response specificity, were investigated in the colon cancer CT26 mouse model. Local treatment prior to DaRT, with the TLR3 agonist poly I:C, was sufficient to inhibit tumor growth relative to poly I:C or DaRT alone. DaRT used in combination with the TLR9 agonist CpG, or with the TLR1/2 agonist XS15 retarded tumor growth and increased tumor-rejection rates, compared to DaRT alone, curing 41% and 20% of the mice, respectively. DaRT in combination with CpG, the Treg inhibitor cyclophosphamide, and the MDSC inhibitor sildenafil, cured 51% of the animals, compared to only 6% and 0% cure when immunomodulation or DaRT was used alone, respectively. Challenge and Winn assays revealed that these high cure rates involved a specific immunological memory against CT26 antigens. We suggest that DaRT acts in synergy with immunomodulation to induce a specific and systemic antitumor immune response. This strategy may serve as a safe and efficient method not only for tumor ablation, but also for in situ vaccination of cancer patients.
Background
The field of robotic surgery has seen significant advancements in the past few years and it has been adopted in many large hospitals in the United States and worldwide as a standard for ...various procedures in recent years. However, the location of many hospitals in urban areas and a lack of surgical expertise in the rural areas could lead to increased travel time and treatment delays for patients in need of robotic surgical management, including cancer patients. The fifth generation (5G) networks have been deployed by various telecom companies in multiple countries worldwide. Our aim is to update the readers about the novel technology and the current scenario of surgical procedures performed using 5G technology. In this article, we also discuss how the technology could aid cancer patients requiring surgical management, the future perspectives, the potential challenges, and the limitations, which would need to overcome prior to widespread real‐life use of the technology for cancer care.
Recent findings
The expansion of 5G technology has enabled some countries to conduct remote surgical procedures, tele‐mentored and real‐time interactive procedures on animal models, cadavers, and humans, demonstrating that 5G networks could offer a potential solution to previously experienced latency and reliability hurdles during the remote surgeries performed in the 2000s.
Conclusion
New technological advancements could serve as a ground for emerging novel therapeutic applications. While limitations and challenges related to the 5G infrastructure, cost, compatibility, and security exist; researching to overcome the limitations and comprehend the potential benefits of integrating the technology into practice would be imminent before widespread clinical use. Remote and tele‐mentored 5G‐powered procedures could offer a new tool in improving the care of patients requiring robotic surgical management such as prostate cancer patients.
The MORC family Li, Da-Qiang; Nair, Sujit S.; Kumar, Rakesh
Epigenetics,
07/2013, Letnik:
8, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Microrchidia (MORC) is a highly conserved nuclear protein superfamily with widespread domain architectures that intimately link MORCs with signaling-dependent chromatin remodeling and epigenetic ...regulation. Accumulating structural and biochemical evidence has shed new light on the mechanistic action and emerging role of MORCs as epigenetic regulators in diverse nuclear processes. In this Point of View, we focus on discussing recent advances in our understanding of the unique domain architectures of MORC family of chromatin remodelers and their potential contribution to epigenetic control of DNA template-dependent processes such as transcription and DNA damage response. Given that the deregulation of MORCs has been linked with human cancer and other diseases, further efforts to uncover the structure and function of MORCs may ultimately lead to the development of new approaches to intersect with the functionality of MORC family of chromatin remodeling proteins to correct associated pathogenesis.
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