Multifaceted Role of PRDM Proteins in Human Cancer

The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention.

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NF-κB and Human Cancer: What Have We Learned over the Past 35 Years?

Biomedicines ◽

10.3390/biomedicines9080889 ◽

2021 ◽

Vol 9 (8) ◽

pp. 889

Author(s):

Thomas D. Gilmore

Keyword(s):

Cell Cycle Progression ◽

Cell Function ◽

Immune Cell ◽

Human Cancer ◽

Cancer Prognosis ◽

Cycle Progression ◽

The Past ◽

Human Cancers ◽

Limited Success ◽

Upstream Regulators

Transcription factor NF-κB has been extensively studied for its varied roles in cancer development since its initial characterization as a potent retroviral oncogene. It is now clear that NF-κB also plays a major role in a large variety of human cancers, including especially ones of immune cell origin. NF-κB is generally constitutively or aberrantly activated in human cancers where it is involved. These activations can occur due to mutations in the NF-κB transcription factors themselves, in upstream regulators of NF-κB, or in pathways that impact NF-κB. In addition, NF-κB can be activated by tumor-assisting processes such as inflammation, stromal effects, and genetic or epigenetic changes in chromatin. Aberrant NF-κB activity can affect many tumor-associated processes, including cell survival, cell cycle progression, inflammation, metastasis, angiogenesis, and regulatory T cell function. As such, inhibition of NF-κB has often been investigated as an anticancer strategy. Nevertheless, with a few exceptions, NF-κB inhibition has had limited success in human cancer treatment. This review covers general themes that have emerged regarding the biological roles and mechanisms by which NF-κB contributes to human cancers and new thoughts on how NF-κB may be targeted for cancer prognosis or therapy.

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Involvement of MicroRNA in Microglia-Mediated Immune Response

Clinical and Developmental Immunology ◽

10.1155/2013/186872 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 44

Author(s):

J. Guedes ◽

A. L. C. Cardoso ◽

M. C. Pedroso de Lima

Keyword(s):

Noncoding Rna ◽

Immune Cell ◽

Regulation Of Gene Expression ◽

Activation Process ◽

Altered Expression ◽

Rna Molecules ◽

Small Noncoding Rna ◽

The Central Nervous System ◽

Therapeutic Tools

MicroRNAs (miRNAs) are an abundant class of small noncoding RNA molecules that play an important role in the regulation of gene expression at the posttranscriptional level. Due to their ability to simultaneously modulate the fate of different genes, these molecules are particularly well suited to act as key regulators during immune cell differentiation and activation, and their dysfunction can contribute to pathological conditions associated with neuroinflammation. Recent studies have addressed the role of miRNAs in the differentiation of progenitor cells into microglia and in the activation process, aiming at clarifying the origin of adult microglia cells and the contribution of the central nervous system (CNS) environment to microglia phenotype, in health and disease. Altered expression of several miRNAs has been associated with Alzheimer’s disease, multiple sclerosis, and ischemic injury, hence strongly advocating the use of these small molecules as disease markers and new therapeutic targets. This review summarizes the recent advances in the field of miRNA-mediated regulation of microglia development and activation. We discuss the role of specific miRNAs in the maintenance and switching of microglia activation states and illustrate the potential of this class of nucleic acids both as biomarkers of inflammation and new therapeutic tools for the modulation of microglia behavior in the CNS.

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Prostate Carcinogenesis: Insights in relation to Epigenetics and Inflammation.

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200719020709 ◽

2020 ◽

Vol 20 ◽

Author(s):

Mirazkar D. Pandareesh ◽

Vivek Hamse Kameshwar ◽

Kullaiah K. Byrappa

Keyword(s):

Prostate Cancer ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Control Cell ◽

Diagnosis And Treatment ◽

Epigenetic Changes ◽

Mesenchymal Transition ◽

Prostate Carcinogenesis ◽

History Of ◽

Clinical Potential

: Prostate cancer is a multifactorial disease that mainly occurs due to the accumulation of somatic, genetic and epigenetic changes, resulting in the inactivation of tumor-suppressor genes and activation of oncogenes. Mutations in genes, specifically those that control cell growth and division or the repair of damaged DNA, make the cells grow and divide uncontrollably to form a tumor. The risk of developing prostate cancer depends upon the gene that has undergone the mutation. Identifying such genetic risk factors for prostate cancer pose a challenge for the researchers. Besides genetic mutations, many epigenetic alterations including DNA methylation, histone modifications (methylation, acetylation, ubiquitylation, sumoylation, and phosphorylation) nucleosomal remodelling, and chromosomal looping, have been significantly contributed to the onset of prostate cancer as well as the prognosis, diagnosis, and treatment of prostate cancer. Chronic inflammation also plays a major role in the onset and progression of human cancer, via. modifications in the tumor microenvironment by initiating epithelial-mesenchymal transition and remodelling the extracellular matrix. In this article, the authors present a brief history of the mechanisms and potential links between the genetic aberrations, epigenetic changes, inflammation and inflammasomes that are known to contribute to the prognosis of prostate cancer. Furthermore, the authors examine and discuss clinical potential of prostate carcinogenesis in relation to epigenetics and inflammation for its diagnosis and treatment.

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Recent Advancements on Immunomodulatory Mechanisms of Resveratrol in Tumor Microenvironment

Molecules ◽

10.3390/molecules26051343 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1343

Author(s):

Gagan Chhabra ◽

Chandra K. Singh ◽

Deeba Amiri ◽

Neha Akula ◽

Nihal Ahmad

Keyword(s):

Tumor Microenvironment ◽

Immune Cell ◽

Cancer Therapies ◽

Regulatory Cells ◽

Immunomodulatory Effects ◽

Cancer Management ◽

Natural Agents ◽

Anticancer Effects ◽

Cancer Types ◽

Immune Related Genes

Immunomodulation of the tumor microenvironment is emerging as an important area of research for the treatment of cancer patients. Several synthetic and natural agents are being investigated for their ability to enhance the immunogenic responses of immune cells present in the tumor microenvironment to impede tumor cell growth and dissemination. Among them, resveratrol, a stilbenoid found in red grapes and many other natural sources, has been studied extensively. Importantly, resveratrol has been shown to possess activity against various human diseases, including cancer. Mechanistically, resveratrol has been shown to regulate an array of signaling pathways and processes involving oxidative stress, inflammation, apoptosis, and several anticancer effects. Furthermore, recent research suggests that resveratrol can regulate various cellular signaling events including immune cell regulation, cytokines/chemokines secretion, and the expression of several other immune-related genes. In this review, we have summarized recent findings on resveratrol’s effects on immune regulatory cells and associated signaling in various cancer types. Numerous immunomodulatory effects of resveratrol suggest it may be useful in combination with other cancer therapies including immunotherapy for effective cancer management.

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STAU2 protein level is controlled by caspases and the CHK1 pathway and regulates cell cycle progression in the non-transformed hTERT-RPE1 cells

BMC Molecular and Cell Biology ◽

10.1186/s12860-021-00352-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Lionel Condé ◽

Yulemi Gonzalez Quesada ◽

Florence Bonnet-Magnaval ◽

Rémy Beaujois ◽

Luc DesGroseillers

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Cell Proliferation ◽

Dna Damage ◽

Steady State ◽

Posttranscriptional Regulation ◽

Cell Cycle Progression ◽

Rna Binding ◽

Regulation Of Gene Expression ◽

Cycle Progression

AbstractBackgroundStaufen2 (STAU2) is an RNA binding protein involved in the posttranscriptional regulation of gene expression. In neurons, STAU2 is required to maintain the balance between differentiation and proliferation of neural stem cells through asymmetric cell division. However, the importance of controlling STAU2 expression for cell cycle progression is not clear in non-neuronal dividing cells. We recently showed that STAU2 transcription is inhibited in response to DNA-damage due to E2F1 displacement from theSTAU2gene promoter. We now study the regulation of STAU2 steady-state levels in unstressed cells and its consequence for cell proliferation.ResultsCRISPR/Cas9-mediated and RNAi-dependent STAU2 depletion in the non-transformed hTERT-RPE1 cells both facilitate cell proliferation suggesting that STAU2 expression influences pathway(s) linked to cell cycle controls. Such effects are not observed in the CRISPR STAU2-KO cancer HCT116 cells nor in the STAU2-RNAi-depleted HeLa cells. Interestingly, a physiological decrease in the steady-state level of STAU2 is controlled by caspases. This effect of peptidases is counterbalanced by the activity of the CHK1 pathway suggesting that STAU2 partial degradation/stabilization fines tune cell cycle progression in unstressed cells. A large-scale proteomic analysis using STAU2/biotinylase fusion protein identifies known STAU2 interactors involved in RNA translation, localization, splicing, or decay confirming the role of STAU2 in the posttranscriptional regulation of gene expression. In addition, several proteins found in the nucleolus, including proteins of the ribosome biogenesis pathway and of the DNA damage response, are found in close proximity to STAU2. Strikingly, many of these proteins are linked to the kinase CHK1 pathway, reinforcing the link between STAU2 functions and the CHK1 pathway. Indeed, inhibition of the CHK1 pathway for 4 h dissociates STAU2 from proteins involved in translation and RNA metabolism.ConclusionsThese results indicate that STAU2 is involved in pathway(s) that control(s) cell proliferation, likely via mechanisms of posttranscriptional regulation, ribonucleoprotein complex assembly, genome integrity and/or checkpoint controls. The mechanism by which STAU2 regulates cell growth likely involves caspases and the kinase CHK1 pathway.

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Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02935-2 ◽

2021 ◽

Author(s):

Rosanna L. Wustrack ◽

Evans Shao ◽

Joey Sheridan ◽

Melissa Zimel ◽

Soo-Jin Cho ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Cd8 T Cells ◽

Tumor Size ◽

Immune Cell ◽

Human Cancer ◽

Soft Tissue Sarcomas ◽

Inverse Correlation ◽

Anatomical Location ◽

Pleomorphic Sarcoma

Abstract Background Soft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited. Methods Here, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients. Results We uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors. Conclusions Our study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.

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Deciphering the Mounting Complexity of the p53 Regulatory Network in Correlation to Long Non-Coding RNAs (lncRNAs) in Ovarian Cancer

Cells ◽

10.3390/cells9030527 ◽

2020 ◽

Vol 9 (3) ◽

pp. 527 ◽

Cited By ~ 10

Author(s):

Sonali Pal ◽

Manoj Garg ◽

Amit Kumar Pandey

Keyword(s):

Ovarian Cancer ◽

Molecular Mechanisms ◽

Human Cancer ◽

Critical Role ◽

Functional Characterization ◽

Great Promise ◽

Altered Expression ◽

Disease Biology ◽

Non Coding Rnas ◽

Post Transcriptional Regulation

Amongst the various gynecological malignancies affecting female health globally, ovarian cancer is one of the predominant and lethal among all. The identification and functional characterization of long non-coding RNAs (lncRNAs) are made possible with the advent of RNA-seq and the advancement of computational logarithm in understanding human disease biology. LncRNAs can interact with deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins and their combinations. Moreover, lncRNAs regulate orchestra of diverse functions including chromatin organization and transcriptional and post-transcriptional regulation. LncRNAs have conferred their critical role in key biological processes in human cancer including tumor initiation, proliferation, cell cycle, apoptosis, necroptosis, autophagy, and metastasis. The interwoven function of tumor-suppressor protein p53-linked lncRNAs in the ovarian cancer paradigm is of paramount importance. Several lncRNAs operate as p53 regulators or effectors and modulates a diverse array of functions either by participating in various signaling cascades or via interaction with different proteins. This review highlights the recent progress made in the identification of p53 associated lncRNAs while elucidating their molecular mechanisms behind the altered expression in ovarian cancer tumorigenesis. Moreover, the development of novel clinical and therapeutic strategies for targeting lncRNAs in human cancers harbors great promise.

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716 Cell-based virotherapy for targeting cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0716 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A758-A758

Author(s):

Duong Nguyen ◽

Alberto Gomez ◽

Forrest Neuharth ◽

Ashley Alamillo ◽

Thomas Herrmann ◽

...

Keyword(s):

Stem Cells ◽

Vaccinia Virus ◽

Cancer Cells ◽

Neutralizing Antibodies ◽

Immune Cell ◽

Human Cancer ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

Adaptive Immune ◽

Immune Barriers

BackgroundOncolytic virotherapy has been recognized as a promising new therapy for cancer for decades but only few viruses have been approved worldwide. The therapeutic potential of oncolytic viruses can be severely restricted by innate and adaptive immune barriers making oncolytic virus clinically inefficient. To overcome this obstacle, we utilized adipose-derived stem cells (AD-MSC) loaded with tumor selective CAL1 oncolytic vaccinia virus to generate a new therapeutic agent called SNV1 (SuperNova-1).MethodsCAL1 vaccinia virus was tested for its ability to replicate and selectively kill various human cancer cell lines in vitro and in vivo. Additionally, CAL1 was loaded into adipose-derived mesenchymal stem cells to generate SuperNova1 (SNV1). Both CAL1 and SNV1 were tested for their ability to kill cancer cells in the presence of active complement and neutralizing antibodies in cell culture as well as in mice. Immune cell infiltration of the treated and untreated tumors was analyzed by flow cytometry.ResultsCAL1 showed preferential amplification and killed various tested human (PC3, FaDu, MDA-MB-231, RPMI) and mouse cancer cells (CT26, EMT6, TRAMP-C2, RM1). In animals, CAL1 caused tumor regression in PC3 and CT26 mouse models without signs of toxicity. SNV1 significantly enhanced protection of CAL1 virus from clearance by the immune system as compared to naked CAL1 virus, leading to higher therapeutic efficacy in animals. Five days after SNV1 administration, tumor infiltrating lymphocytes (TILs) from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations. Importantly, we documented a decreased frequency of Tregs, and improved effector to Treg ratios, which was associated with inhibition of tumor growth at the treated tumor site and also at distant untreated sites.ConclusionsCAL1 is potentially used as an oncolytic agent. In addition, SNV1 cell-based platform protects and potentiates oncolytic vaccinia virus by circumventing humoral innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy. Particularly, SNV1 provided instantly active viral particles for immediate infection and simultaneous release of therapeutic proteins in the injected tumors.

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The nucleoplasmic interactions among Lamin A/C-pRB-LAP2α-E2F1 are modulated by dexamethasone

Scientific Reports ◽

10.1038/s41598-021-89608-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anastasia Ricci ◽

Sara Orazi ◽

Federica Biancucci ◽

Mauro Magnani ◽

Michele Menotta

Keyword(s):

Gene Expression ◽

Cell Cycle Progression ◽

Regulation Of Gene Expression ◽

Lamin A ◽

Wild Type ◽

Cycle Progression ◽

C Dynamics ◽

E2f Transcription Factor ◽

Transcription Factor 1

AbstractAtaxia telangiectasia (AT) is a rare genetic neurodegenerative disease. To date, there is no available cure for the illness, but the use of glucocorticoids has been shown to alleviate the neurological symptoms associated with AT. While studying the effects of dexamethasone (dex) in AT fibroblasts, by chance we observed that the nucleoplasmic Lamin A/C was affected by the drug. In addition to the structural roles of A-type lamins, Lamin A/C has been shown to play a role in the regulation of gene expression and cell cycle progression, and alterations in the LMNA gene is cause of human diseases called laminopathies. Dex was found to improve the nucleoplasmic accumulation of soluble Lamin A/C and was capable of managing the large chromatin Lamin A/C scaffolds contained complex, thus regulating epigenetics in treated cells. In addition, dex modified the interactions of Lamin A/C with its direct partners lamin associated polypeptide (LAP) 2a, Retinoblastoma 1 (pRB) and E2F Transcription Factor 1 (E2F1), regulating local gene expression dependent on E2F1. These effects were differentially observed in both AT and wild type (WT) cells. To our knowledge, this is the first reported evidence of the role of dex in Lamin A/C dynamics in AT cells, and may represent a new area of research regarding the effects of glucocorticoids on AT. Moreover, future investigations could also be extended to healthy subjects or to other pathologies such as laminopathies since glucocorticoids may have other important effects in these contexts as well.

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