Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC

Aberrant telomerase reverse transcriptase (TERT) expression is crucial for tumor survival and cancer cells escaping apoptosis. Multiple TERT-locus variants at 5p15 have been discovered in association with cancer risk, yet the underlying mechanisms and clinical impacts remain unclear. Here, our association studies showed that the TERT promoter variant rs2853669 confers a risk of prostate cancer (PCa) in different ethnic groups. Further functional investigation revealed that the allele-specific binding of MYC and E2F1 at TERT promoter variant rs2853669 associates with elevated level of TERT in PCa. Mechanistically, androgen stimulations promoted the binding of MYC to allele T of rs2853669, thereby activating TERT, whereas hormone deprivations enhanced E2F1 binding at allele C of rs2853669, thus upregulating TERT expression. Notably, E2F1 could cooperate with AR signaling to regulate MYC expression. Clinical data demonstrated synergistic effects of MYC/E2F1/TERT expression or with the TT and CC genotype of rs2853669 on PCa prognosis and severity. Strikingly, single-nucleotide editing assays showed that the CC genotype of rs2853669 obviously promotes epithelial–mesenchymal transition (EMT) and the development of castration-resistant PCa (CRPC), confirmed by unbiased global transcriptome profiling. Our findings thus provided compelling evidence for understanding the roles of noncoding variations coordinated with androgen signaling and oncogenic transcription factors in mis-regulating TERT expression and driving PCa.

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Magnesium Chloride is an Effective Therapeutic Agent for Prostate Cancer

Functional Foods in Health and Disease ◽

10.31989/ffhd.v8i1.368 ◽

2018 ◽

Vol 8 (1) ◽

pp. 62 ◽

Cited By ~ 2

Author(s):

Julianna Maria Santos ◽

Fazle Hussain

Keyword(s):

Prostate Cancer ◽

Magnesium Chloride ◽

Epithelial Mesenchymal Transition ◽

Chromatin Condensation ◽

Myosin Ii ◽

In Vivo Studies ◽

Migration Speed ◽

Mesenchymal Transition

Background: Reduced levels of magnesium can cause several diseases and increase cancer risk. Motivated by magnesium chloride’s (MgCl2) non-toxicity, physiological importance, and beneficial clinical applications, we studied its action mechanism and possible mechanical, molecular, and physiological effects in prostate cancer with different metastatic potentials.Methods: We examined the effects of MgCl2, after 24 and 48 hours, on apoptosis, cell migration, expression of epithelial mesenchymal transition (EMT) markers, and V-H+-ATPase, myosin II (NMII) and the transcription factor NF Kappa B (NFkB) expressions.Results: MgCl2 induces apoptosis, and significantly decreases migration speed in cancer cells with different metastatic potentials. MgCl2 reduces the expression of V-H+-ATPase and myosin II that facilitates invasion and metastasis, suppresses the expression of vimentin and increases expression of E-cadherin, suggesting a role of MgCl2 in reversing the EMT. MgCl2 also significantly increases the chromatin condensation and decreases NFkB expression.Conclusions: These results suggest a promising preventive and therapeutic role of MgCl2 for prostate cancer. Further studies should explore extending MgCl2 therapy to in vivo studies and other cancer types.Keywords: Magnesium chloride, prostate cancer, migration speed, V-H+-ATPase, and EMT.

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Development of a Novel Method to Detect Prostate Cancer Circulating Tumor Cells (CTCs) Based on Epithelial-Mesenchymal Transition Biology

10.21236/ada612115 ◽

2014 ◽

Author(s):

Andrew J. Armstrong

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Detect Prostate Cancer ◽

Novel Method

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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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Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽

10.1038/s41388-021-01887-2 ◽

2021 ◽

Author(s):

Kaisa-Mari Launonen ◽

Ville Paakinaho ◽

Gianluca Sigismondo ◽

Marjo Malinen ◽

Reijo Sironen ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Protein A ◽

Chorioallantoic Membrane ◽

Chromatin Accessibility ◽

Castration Resistant Prostate Cancer ◽

Novel Therapy ◽

Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

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MicroRNA-144 Suppresses Prostate Cancer Growth and Metastasis by Targeting EZH2

Technology in Cancer Research & Treatment ◽

10.1177/1533033821989817 ◽

2021 ◽

Vol 20 ◽

pp. 153303382198981

Author(s):

Xin-bo Sun ◽

Yong-wei Chen ◽

Qi-sheng Yao ◽

Xu-hua Chen ◽

Min He ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Viability ◽

Cell Apoptosis ◽

Epithelial Mesenchymal Transition ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Proliferation And Apoptosis ◽

High Incidence ◽

Inhibit Cell Proliferation

Background: Prostate cancer is a common malignant tumor with a high incidence. MicroRNAs (miRNAs) have been shown to be important post-transcriptional regulators during tumorigenesis. This study aimed to explore the effect of miR-144 on PCa proliferation and apoptosis. Material and Methods: The expression of miR-144 and EZH2 were examined in clinical PCa tissues. PCa cell line LNCAP and DU-145 was employed and transfected with miR-144 mimics or inhibitors. The correlation between miR-144 and EZH2 was verified by luciferase reporter assay. Cell viability, apoptosis and migratory capacity were detected by CCK-8, flow cytometry assay and wound healing assay. The protein level of EZH2, E-Cadherin, N-Cadherin and vimentin were analyzed by western blotting. Results: miR-144 was found to be negatively correlated to the expression of EZH2 in PCa tissues. Further studies identified EZH2 as a direct target of miR-144. Moreover, overexpression of miR-144 downregulated expression of EZH2, reduced cell viability and promoted cell apoptosis, while knockdown of miR-144 led to an inverse result. miR-144 also suppressed epithelial-mesenchymal transition level of PCa cells. Conclusion: Our study indicated that miR-144 negatively regulate the expression of EZH2 in clinical specimens and in vitro. miR-144 can inhibit cell proliferation and induce cell apoptosis in PCa cells. Therefore, miR-144 has the potential to be used as a biomarker for predicting the progression of PCa.

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Correction to: Inactivation of the Wnt/β-catenin signaling pathway underlies inhibitory role of microRNA-129-5p in epithelial–mesenchymal transition and angiogenesis of prostate cancer by targeting ZIC2

Cancer Cell International ◽

10.1186/s12935-021-01945-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhenming Jiang ◽

Yuxi Zhang ◽

Xi Chen ◽

Pingeng Wu ◽

Dong Chen

Keyword(s):

Prostate Cancer ◽

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Inhibitory Role

An amendment to this paper has been published and can be accessed via the original article.

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Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cancers ◽

10.3390/cancers13112795 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2795

Author(s):

Sofia Papanikolaou ◽

Aikaterini Vourda ◽

Spyros Syggelos ◽

Kostis Gyftopoulos

Keyword(s):

Prostate Cancer ◽

Cancer Therapy ◽

Tumor Progression ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Therapy Resistance ◽

Cellular Process ◽

Cell Plasticity ◽

Mesenchymal Transition

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.

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Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma

Digestive Diseases ◽

10.1159/000439102 ◽

2015 ◽

Vol 33 (6) ◽

pp. 771-779 ◽

Cited By ~ 45

Author(s):

Naoshi Nishida ◽

Masayuki Kitano ◽

Toshiharu Sakurai ◽

Masatoshi Kudo

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factor ◽

Kinase Inhibitor ◽

Epithelial Mesenchymal Transition ◽

Growth Factor Receptor ◽

Stem Cell Markers ◽

Mesenchymal Transition ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Underlying Mechanisms

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC.

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