Reciprocal Interconnection of miRNome-Epigenome in Cancer Pathogenesis and Its Therapeutic Potential

Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism is essential for genome integrity and for preventing progression to cellular senescence or tumorigenesis. NAD+is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD+decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD+precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis.

Download Full-text

TGFβ signaling regulates epithelial–mesenchymal plasticity in ovarian cancer ascites-derived spheroids

Endocrine Related Cancer ◽

10.1530/erc-15-0383 ◽

2015 ◽

Vol 23 (3) ◽

pp. 147-159 ◽

Cited By ~ 33

Author(s):

Samah Rafehi ◽

Yudith Ramos Valdes ◽

Monique Bertrand ◽

Jacob McGee ◽

Michel Préfontaine ◽

...

Keyword(s):

Ovarian Cancer ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Potential ◽

Type I ◽

Tgfβ Signaling ◽

Mesenchymal Transition ◽

Tumor Cell Migration ◽

Cancer Pathogenesis

Epithelial–mesenchymal transition (EMT) serves as a key mechanism driving tumor cell migration, invasion, and metastasis in many carcinomas. Transforming growth factor-beta (TGFβ) signaling is implicated in several steps during cancer pathogenesis and acts as a classical inducer of EMT. Since epithelial ovarian cancer (EOC) cells have the potential to switch between epithelial and mesenchymal states during metastasis, we predicted that modulation of TGFβ signaling would significantly impact EMT and the malignant potential of EOC spheroid cells. Ovarian cancer patient ascites-derived cells naturally underwent an EMT response when aggregating into spheroids, and this was reversed upon spheroid re-attachment to a substratum. CDH1/E-cadherin expression was markedly reduced in spheroids compared with adherent cells, in concert with an up-regulation of several transcriptional repressors, i.e., SNAI1/Snail, TWIST1/2, and ZEB2. Treatment of EOC spheroids with the TGFβ type I receptor inhibitor, SB-431542, potently blocked the endogenous activation of EMT in spheroids. Furthermore, treatment of spheroids with SB-431542 upon re-attachment enhanced the epithelial phenotype of dispersing cells and significantly decreased cell motility and Transwell migration. Spheroid formation was significantly compromised by exposure to SB-431542 that correlated with a reduction in cell viability particularly in combination with carboplatin treatment. Thus, our findings are the first to demonstrate that intact TGFβ signaling is required to control EMT in EOC ascites-derived cell spheroids, and it promotes the malignant characteristics of these structures. As such, we show the therapeutic potential for targeted inhibition of this pathway in ovarian cancer patients with late-stage disease.

Download Full-text

Biological Functions of Gasdermins in Cancer: From Molecular Mechanisms to Therapeutic Potential

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.638710 ◽

2021 ◽

Vol 9 ◽

Author(s):

Man Wang ◽

Xinzhe Chen ◽

Yuan Zhang

Keyword(s):

Cell Death ◽

Cancer Cell ◽

Cancer Progression ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Effector Proteins ◽

Biological Functions ◽

Cancer Cell Growth ◽

Cancer Pathogenesis

Pyroptosis is a type of lytic programmed cell death triggered by various inflammasomes that sense danger signals. Pyroptosis has recently attracted great attention owing to its contributory role in cancer. Pyroptosis plays an important role in cancer progression by inducing cancer cell death or eliciting anticancer immunity. The participation of gasdermins (GSDMs) in pyroptosis is a noteworthy recent discovery. GSDMs have emerged as a group of pore-forming proteins that serve important roles in innate immunity and are composed of GSDMA-E and Pejvakin (PJVK) in human. The N-terminal domains of GSDMs, expect PJVK, can form pores on the cell membrane and function as effector proteins of pyroptosis. Remarkably, it has been found that GSDMs are abnormally expressed in several forms of cancers. Moreover, GSDMs are involved in cancer cell growth, invasion, metastasis and chemoresistance. Additionally, increasing evidence has indicated an association between GSDMs and clinicopathological features in cancer patients. These findings suggest the feasibility of using GSDMs as prospective biomarkers for cancer diagnosis, therapeutic intervention and prognosis. Here, we review the progress in unveiling the characteristics and biological functions of GSDMs. We also focus on the implication and molecular mechanisms of GSDMs in cancer pathogenesis. Investigating the relationship between GSDMs and cancer biology could assist us to explore new therapeutic avenues for cancer prevention and treatment.

Download Full-text

Poly(ADP-Ribose) Polymerase in Cervical Cancer Pathogenesis: Mechanism and Potential Role for PARP Inhibitors

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000654 ◽

2016 ◽

Vol 26 (4) ◽

pp. 763-769 ◽

Cited By ~ 6

Author(s):

Ioannis C. Kotsopoulos ◽

Ali Kucukmetin ◽

Asima Mukhopadhyay ◽

John Lunec ◽

Nicola J. Curtin

Keyword(s):

Cervical Cancer ◽

Therapeutic Potential ◽

Treatment Options ◽

Invasive Cervical Cancer ◽

Locally Advanced ◽

Intraepithelial Neoplasia ◽

Parp Inhibitors ◽

Chemotherapeutic Agents ◽

Cancer Pathogenesis

AbstractTreatment options for disease recurrence of women treated for locally advanced and advanced cervical cancer are very limited—largely palliative chemotherapy. The low efficacy of the currently available drugs raises the need for new targeted agents. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutic agents in cancers associated with defects in DNA repair. Their therapeutic potential in cervical cancer is currently being evaluated in 3 ongoing clinical trials. Here we review the available information regarding all the aspects of PARP in cervical intraepithelial neoplasia and invasive cervical cancer, from expression and the mechanism of action to the role of the polymorphisms in the pathogenesis of the disease, as well as the potential of the inhibitors. We finally propose a new unifying theory regarding the role of PARPs in the development of cervical carcinomas.

Download Full-text

Potential Role of Peptidylarginine Deiminase Enzymes and Protein Citrullination in Cancer Pathogenesis

Biochemistry Research International ◽

10.1155/2012/895343 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 63

Author(s):

Sunish Mohanan ◽

Brian D. Cherrington ◽

Sachi Horibata ◽

John L. McElwee ◽

Paul R. Thompson ◽

...

Keyword(s):

Tumor Cell ◽

Tumor Progression ◽

Cell Lines ◽

Potential Role ◽

Therapeutic Potential ◽

Multiple Tumor ◽

Cancer Pathogenesis ◽

Specific Distribution ◽

And Function

The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein-bound arginine and methylarginine residues to the uncharged, nonstandard amino acid citrulline. This enzymatic activity is referred to as citrullination or, alternatively, deimination. Citrullination can significantly affect biochemical pathways by altering the structure and function of target proteins. Five mammalian PAD family members (PADs 1–4 and 6) have been described and show tissue-specific distribution. Recent reviews on PADs have focused on their role in autoimmune diseases. Here, we will discuss the potential role of PADs in tumor progression and tumor-associated inflammation. In the context of cancer, increasing clinical evidence suggests that PAD4 (and possibly PAD2) has important roles in tumor progression. The link between PADs and cancer is strengthened by recent findings showing that treatment of cell lines and mice with PAD inhibitors significantly suppresses tumor growth and, interestingly, inflammatory symptoms. At the molecular level, transcription factors, coregulators, and histones are functional targets for citrullination by PADs, and citrullination of these targets can affect gene expression in multiple tumor cell lines. Next generation isozyme-specific PAD inhibitors may have therapeutic potential to regulate both the inflammatory tumor microenvironment and tumor cell growth.

Download Full-text

Gut microbiota-mediated immunomodulation in tumor

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01983-x ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xinyi Liu ◽

Yanjie Chen ◽

Si Zhang ◽

Ling Dong

Keyword(s):

Gut Microbiota ◽

Tumor Immunity ◽

Cancer Progression ◽

Therapeutic Potential ◽

Checkpoint Inhibitors ◽

Microbial Composition ◽

Metagenome Analysis ◽

Physiological Processes ◽

Cancer Pathogenesis ◽

Significant Difference

AbstractTumor immunity consists of various types of cells, which serve an important role in antitumor therapy. The gastrointestinal tract is colonized by trillions of microorganisms, which form the gut microbiota. In addition to pathogen defense and maintaining the intestinal ecosystem, gut microbiota also plays a pivotal role in various physiological processes. Recently, the association between these symbionts and cancer, ranging from oncogenesis and cancer progression to resistance or sensitivity to antitumor therapies, has attracted much attention. Metagenome analysis revealed a significant difference between the gut microbial composition of cancer patients and healthy individuals. Moreover, modulation of microbiome could improve therapeutic response to immune checkpoint inhibitors (ICIs). These findings suggest that microbiome is involved in cancer pathogenesis and progression through regulation of tumor immunosurveillance, although the exact mechanisms remain largely unknown. This review focuses on the interaction between the microbiome and tumor immunity, with in-depth discussion regarding the therapeutic potential of modulating gut microbiota in ICIs. Further investigations are warranted before gut microbiota can be introduced into clinical practice.

Download Full-text

Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning

Cells ◽

10.3390/cells10113137 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3137

Author(s):

Juan Pablo Rigalli ◽

Dirk Theile ◽

Julie Nilles ◽

Johanna Weiss

Keyword(s):

Gene Expression ◽

Target Genes ◽

Therapeutic Potential ◽

Chromatin Condensation ◽

Critical Role ◽

Pregnane X Receptor ◽

Histone Deacetylation ◽

Regulatory Function ◽

Mediated Effects ◽

Cancer Pathogenesis

The pregnane X receptor (PXR, NR1I2) is a nuclear receptor which exerts its regulatory function by heterodimerization with the retinoid-X-receptor α (RXRα, NR2B1) and binding to the promoter and enhancer regions of diverse target genes. PXR is involved in the regulation of drug metabolism and excretion, metabolic and immunological functions and cancer pathogenesis. PXR activity is strongly regulated by the association with coactivator and corepressor proteins. Coactivator proteins exhibit histone acetyltransferase or histone methyltransferase activity or associate with proteins having one of these activities, thus promoting chromatin decondensation and activation of the gene expression. On the contrary, corepressor proteins promote histone deacetylation and therefore favor chromatin condensation and repression of the gene expression. Several studies pointed to clear cell- and ligand-specific differences in the activation of PXR. In this article, we will review the critical role of coactivator and corepressor proteins as molecular determinants of the specificity of PXR-mediated effects. As already known for other nuclear receptors, understanding the complex mechanism of PXR activation in each cell type and under particular physiological and pathophysiological conditions may lead to the development of selective modulators with therapeutic potential.

Download Full-text