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Epigenetic and Transcriptional Mechanisms in Gynecologic Cancers Development, Progression, and Resistance to Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 17351

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Dr. Maciej Skrzypczak

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Second Department of Gynecology, Lublin Medical University, Jaczewski Street 8, 20-954 Lublin, Poland
Interests: ovarian cancer
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Epigenetic changes represent mechanisms that can regulate cell fate in different mode of action. The affected cell can either undergo apoptosis or proliferation, depending on the epigenetic modulators affected. It is now widely believed that epigenetics is involved in the pathogenesis of many disorders, including gynaecological cancers, like ovarian cancer, endometrial cancer, breast cancer, vulvar cancer, cervical cancer, sarcomas. Early research into epigenetic disease in cancer focused on single gene methylation patterns.

However, newer genome-wide methods have identified a group of genes and enzymes whose regulation is epigenetically altered during the disease progression. DNA methyltransferases(DNMTs) and histone deacetylases (HDACs) are one of the key enzymes mediating epigenetic regulation of gene expression. Its improper function results in DNA hypermethylation and/or histone deacetylation in gene promoter regions that is associated with a reduction or silencing of transcription. DNMT and HDAC inhibitors induce DNA demethylation and histone acetylation, respectively, leading to reactivation of silenced genes and dramatic morphological and functional changes in cancer cells. The potential reversibility of epigenetic mechanisms makes them attractive candidates for the prevention and/or treatment. Detecting the epigenetic signature specific for particular gynaecological cancers could be useful in identifying potential biomarkers for disease detection, classification, monitoring, as well as could facilitate personalized treatment.

Dr. Maciej Skrzypczak
Guest Editor

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Keywords

epigenetics
DNA demethylation
DNA methyltransferases(DNMTs)
histone deacetylases (HDACs)
gynaecological cancers
ovarian cancer
endometrial cancer
breast cancer
vulvar cancer
cervical cancer
sarcomas
personalized treatment

Published Papers (6 papers)

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Research

14 pages, 3258 KiB

Open AccessArticle

Splicing Characterization and Isoform Switch Events in Human Keratinocytes Carrying Oncogenes from High-Risk HPV-16 and Low-Risk HPV-84

by Maryam Nasiri-Aghdam, Mariel Garcia-Chagollan, Ana Laura Pereira-Suarez, Adriana Aguilar-Lemarroy and Luis Felipe Jave-Suarez

Int. J. Mol. Sci. 2023, 24(9), 8347; https://doi.org/10.3390/ijms24098347 - 6 May 2023

Viewed by 1593

Abstract

Infection of epithelial cells with high-risk HPV (HR-HPV) types, followed by expression of virus oncogenic proteins (E5, E6, and E7), leads to genomic imbalance, suppression of tumor inhibitors, and induction of oncogenes. Low-risk HPV (LR-HPV) may slow the rate at which cervical cancer spreads to an invasive stage since co-infection with LR-HPV is linked to a decreased risk of future invasive cancer than infection with HR-HPV alone. We then propose that cancer-progressing changes may be distinguished through identifying the functional differences between LR-HPV and HR-HPV. Lentiviral strategies were followed to establish HaCaT cells with constitutive expression of HPV oncogenes. RNAseq experiments were designed to analyze the transcriptome modulations caused by each of the E5, E6, and E7 oncogenes of HPV-16 and HPV-84 in HaCaT cells. We identified enhanced RNA degradation, spliceosome, and RNA polymerase pathways related to mRNA processing. ATTS (alternative transcription termination site) was discovered to be more prevalent in cells with HPV-16E5 than HPV-84E5. In HPV-16E6-infected cells, ATTS gain was significantly higher than ATTS loss. Cells with HPV-16E7 had more isoforms with intron retention (IR) than those with HPV-84E7. We identified switches in ADAM10, CLSPN, and RNPS1 that led to greater expression of the coding isoforms in HR-HPV. The results of this work highlight differences between LR-HPV and HR-HPV in mRNA processing. Moreover, crucial cervical cancer-related switch events were detected. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Mechanisms in Gynecologic Cancers Development, Progression, and Resistance to Treatment)

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17 pages, 4849 KiB

Open AccessArticle

The Functional Role and Regulatory Mechanism of FTO m⁶A RNA Demethylase in Human Uterine Leiomyosarcoma

by Qiwei Yang and Ayman Al-Hendy

Int. J. Mol. Sci. 2023, 24(9), 7957; https://doi.org/10.3390/ijms24097957 - 27 Apr 2023

Cited by 2 | Viewed by 1656

Abstract

Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis and high rates of recurrence and metastasis. The origin and molecular mechanism underlying and driving its clinical and biological behavior remain largely unknown. Recently, we and others have revealed the role of microRNAs, DNA methylation, and histone modifications in contributing to the pathogenesis of uLMS. However, the connection between reversible m⁶A RNA methylation and uLMS pathogenesis remains unclear. In this study, we assessed the role and mechanism of FTO m⁶A RNA demethylase in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that the levels of RNA demethylases FTO and ALKBH5 were aberrantly upregulated in uLMS tissues compared to adjacent myometrium with a significant change by histochemical scoring assessment (p < 0.01). Furthermore, the inhibition of FTO demethylase with its small, potent inhibitor (Dac51) significantly decreased the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-seq analysis revealed that the inhibition of FTO with Dac51 exhibited a significant decrease in cell-cycle-related genes, including several CDK members, and a significant increase in the expression of CDKN1A, which correlated with a Dac51-exerted inhibitory effect on cell proliferation. Moreover, Dac51 treatment allowed the rewiring of several critical pathways, including TNFα signaling, KRAS signaling, inflammation response, G₂M checkpoint, and C-Myc signaling, among others, leading to the suppression of the uLMS phenotype. Moreover, transcription factor (TF) analyses suggested that epitranscriptional alterations by Dac51 may alter the cell cycle-related gene expression via TF-driven pathways and epigenetic networks in uLMS cells. This intersection of RNA methylation and other epigenetic controls and pathways provides a framework to better understand uterine diseases, particularly uLMS pathogenesis with a dysregulation of RNA methylation machinery. Therefore, targeting the vulnerable epitranscriptome may provide an additional regulatory layer for a promising and novel strategy for treating patients with this aggressive uterine cancer. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Mechanisms in Gynecologic Cancers Development, Progression, and Resistance to Treatment)

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12 pages, 2088 KiB

Open AccessArticle

Peripheral mRNA Expression and Prognostic Significance of Emotional Stress Biomarkers in Metastatic Breast Cancer Patients

by Tahreem Fiaz, Muhammad Shahid Nadeem, Obaid Afzal, Abdulmalik S. A. Altamimi, Sami I. Alzarea, Waleed Hassan Almalki, Hafsa Ahmed Khan, Iahtisham-Ul-Haq, Sharoon Hanook, Imran Kazmi and Muhammad Mustafa

Int. J. Mol. Sci. 2022, 23(22), 14097; https://doi.org/10.3390/ijms232214097 - 15 Nov 2022

Cited by 2 | Viewed by 2188

Abstract

Emotional stress is believed to be associated with increased tumor progression. Stress-induced epigenetic modifications can contribute to the severity of disease and poor prognosis in cancer patients. The current study aimed to investigate the expression profiles along with the prognostic significance of psychological stress-related genes in metastatic breast cancer patients, to rationalize the molecular link between emotional stress and cancer progression. We profiled the expression of selected stress-associated genes (5-HTT, NR3C1, OXTR, and FKBP5) in breast cancer including the stress evaluation of all participants using the Questionnaire on Distress in Cancer Patients–short form (QSC-R10). A survival database, the Kaplan–Meier Plotter, was used to explore the prognostic significance of these genes in breast cancer. Our results showed relatively low expressions of 5-HTT (p = 0.02) and OXTR (p = 0.0387) in metastatic breast cancer patients as compared to the non-metastatic group of patients. The expression of NR3C1 was low in tumor grade III as compared to grade II (p = 0.04). Additionally, the expression of NR3C1 was significantly higher in patients with positive estrogen receptor status. However, no significant difference was found regarding FKBP5 expression in breast cancer. The results suggest a potential implication of these genes in breast cancer pathology and prognosis. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Mechanisms in Gynecologic Cancers Development, Progression, and Resistance to Treatment)

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15 pages, 3139 KiB

Open AccessArticle

Mechano-Sensing Channel PIEZO2 Enhances Invasive Phenotype in Triple-Negative Breast Cancer

by Eriko Katsuta, Kazuaki Takabe, Marija Vujcic, Philip A. Gottlieb, Tao Dai, Arnaldo Mercado-Perez, Arthur Beyder, Qingfei Wang and Mateusz Opyrchal

Int. J. Mol. Sci. 2022, 23(17), 9909; https://doi.org/10.3390/ijms23179909 - 31 Aug 2022

Cited by 9 | Viewed by 2756

Abstract

Background: Mechanically gated PIEZO channels lead to an influx of cations, activation of additional Ca²⁺ channels, and cell depolarization. This study aimed to investigate PIEZO2’s role in breast cancer. Methods: The clinical relevance of PIEZO2 expression in breast cancer patient was analyzed in a publicly available dataset. Utilizing PIEZO2 overexpressed breast cancer cells, and in vitro and in vivo experiments were conducted. Results: High expression of PIEZO2 was correlated with a worse survival in triple-negative breast cancer (TNBC) but not in other subtypes. Increased PEIZO2 channel function was confirmed in PIEZO2 overexpressed cells after mechanical stimulation. PIEZO2 overexpressed cells showed increased motility and invasive phenotypes as well as higher expression of SNAIL and Vimentin and lower expression of E-cadherin in TNBC cells. Correspondingly, high expression of PIEZO2 was correlated with the increased expression of epithelial–mesenchymal transition (EMT)-related genes in a TNBC patient. Activated Akt signaling was observed in PIEZO2 overexpressed TNBC cells. PIEZO2 overexpressed MDA-MB-231 cells formed a significantly higher number of lung metastases after orthotopic implantation. Conclusion: PIEZO2 activation led to enhanced SNAIL stabilization through Akt activation. It enhanced Vimentin and repressed E-cadherin transcription, resulting in increased metastatic potential and poor clinical outcomes in TNBC patients. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Mechanisms in Gynecologic Cancers Development, Progression, and Resistance to Treatment)

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21 pages, 8092 KiB

Open AccessArticle

RNA Editing Enzyme ADAR1 Regulates METTL3 in an Editing Dependent Manner to Promote Breast Cancer Progression via METTL3/ARHGAP5/YTHDF1 Axis

by Yi Li, Ning-Xi Wang, Chuan Yin, Shan-Shan Jiang, Jia-Chu Li and Sheng-Yong Yang

Int. J. Mol. Sci. 2022, 23(17), 9656; https://doi.org/10.3390/ijms23179656 - 25 Aug 2022

Cited by 14 | Viewed by 6323

Abstract

A-to-I RNA editing and m⁶A modification are two of the most prevalent types of RNA modifications controlling gene expression in mammals and play very important roles in tumorigenesis and tumor progression. However, the functional roles and correlations of these two RNA modifications remain to be further investigated in cancer. Herein, we show that ADAR1, an A-to-I RNA-editing enzyme, interacts with METTL3 and increases its protein level to promote the proliferation, migration and invasion of breast cancer cells through a mechanism connecting ADAR1, METTL3 and YTHDF1. We show that both ADAR1 and METTL3 are upregulated in breast cancer samples, and ADAR1 positively correlates with METTL3; ADAR1 edits METTL3 mRNA and changes its binding site to miR532-5p, leading to increased METTL3 protein, which further targets ARHGAP5, recognized by YTHDF1. Additionally, we show that loss of ADAR1 significantly inhibits breast cancer growth in vivo. Collectively, our findings identify the ADAR1–METTL3 axis as a novel, important pathway that connects A-to-I editing and m⁶A RNA modifications during breast cancer progression. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Mechanisms in Gynecologic Cancers Development, Progression, and Resistance to Treatment)

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16 pages, 3040 KiB

Open AccessArticle

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

by Ji Yoon Kim, Seung Yoon Han, Jung Yoo, Go Woon Kim, Yu Hyun Jeon, Sang Wu Lee, Jongsun Park and So Hee Kwon

Int. J. Mol. Sci. 2022, 23(15), 8645; https://doi.org/10.3390/ijms23158645 - 3 Aug 2022

Cited by 7 | Viewed by 2194

Abstract

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors. Full article

(This article belongs to the Special Issue Epigenetic and Transcriptional Mechanisms in Gynecologic Cancers Development, Progression, and Resistance to Treatment)

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