scholarly journals A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1152
Author(s):  
Anna Melekhova ◽  
Mirjam Leeder ◽  
Thanakorn Pungsrinont ◽  
Tim Schmäche ◽  
Julia Kallenbach ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Splice Variant ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Tumour Suppressor ◽  
Survival Prognosis ◽  
Mesenchymal Transition ◽  
Plant Homeodomain ◽  
The Impact ◽  
Emt Markers

Inhibitor of growth 3 (ING3) is one of five members of the ING tumour suppressor family, characterized by a highly conserved plant homeodomain (PHD) as a reader of the histone mark H3K4me3. ING3 was reported to act as a tumour suppressor in many different cancer types to regulate apoptosis. On the other hand, ING3 levels positively correlate with poor survival prognosis of prostate cancer (PCa) patients. In PCa cells, ING3 acts rather as an androgen receptor (AR) co-activator and harbours oncogenic properties in PCa. Here, we show the identification of a novel ING3 splice variant in both the human PCa cell line LNCaP and in human PCa patient specimen. The novel ING3 splice variant lacks exon 11, ING3∆ex11, which results in deletion of the PHD, providing a unique opportunity to analyse functionally the PHD of ING3 by a natural splice variant. Functionally, overexpression of ING3Δex11 induced morphological changes of LNCaP-derived 3D spheroids with generation of lumen and pore-like structures within spheroids. Since these structures are an indicator of epithelial–mesenchymal transition (EMT), key regulatory factors and markers for EMT were analysed. The data suggest that in contrast to ING3, ING3Δex11 specifically modulates the expression of key EMT-regulating upstream transcription factors and induces the expression of EMT markers, indicating that the PHD of ING3 inhibits EMT. In line with this, ING3 knockdown also induced the expression of EMT markers, confirming the impact of ING3 on EMT regulation. Further, ING3 knockdown induced cellular senescence via a pathway leading to cell cycle arrest, indicating an oncogenic role for ING3 in PCa. Thus, the data suggest that the ING3Δex11 splice variant lacking functional PHD exhibits oncogenic characteristics through triggering EMT in PCa cells.

THE IMPACT OF DAB2IP ON EPITHELIAL-MESENCHYMAL TRANSITION (EMT) LEADING TO PROSTATE CANCER METASTASIS

2009 ◽  
Vol 181 (4S) ◽  
pp. 512-512
Author(s):  
Daxing Xie ◽  
Jun Liu ◽  
Crystal Gore ◽  
Guiyang Hao ◽  
Michael Long ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Prostate Cancer Metastasis ◽  
The Impact

scholarly journals The paracrine induction of prostate cancer progression by caveolin-1

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Chun-Jung Lin ◽  
Eun-Jin Yun ◽  
U-Ging Lo ◽  
Yu-Ling Tai ◽  
Su Deng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cell ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Neuroendocrine Differentiation ◽  
Small Subset ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
The Impact

Abstract A subpopulation of cancer stem cells (CSCs) plays a critical role of cancer progression, recurrence, and therapeutic resistance. Many studies have indicated that castration-resistant prostate cancer (CRPC) is associated with stem cell phenotypes, which could further promote neuroendocrine transdifferentiation. Although only a small subset of genetically pre-programmed cells in each organ has stem cell capability, CSCs appear to be inducible among a heterogeneous cancer cell population. However, the inductive mechanism(s) leading to the emergence of these CSCs are not fully understood in CRPC. Tumor cells actively produce, release, and utilize exosomes to promote cancer development and metastasis, cancer immune evasion as well as chemotherapeutic resistance; the impact of tumor-derived exosomes (TDE) and its cargo on prostate cancer (PCa) development is still unclear. In this study, we demonstrate that the presence of Cav-1 in TDE acts as a potent driver to induce CSC phenotypes and epithelial–mesenchymal transition in PCa undergoing neuroendocrine differentiation through NFκB signaling pathway. Furthermore, Cav-1 in mCRPC-derived exosomes is capable of inducing radio- and chemo-resistance in recipient cells. Collectively, these data support Cav-1 as a critical driver for mCRPC progression.

scholarly journals Androgen Receptor Splice Variant AR3 Promotes Prostate Cancer via Modulating Expression of Autocrine/Paracrine Factors

2013 ◽  
Vol 289 (3) ◽  
pp. 1529-1539 ◽  
Author(s):  
Feng Sun ◽  
He-ge Chen ◽  
Wei Li ◽  
Xi Yang ◽  
Xin Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Splice Variant ◽  
Epithelial Mesenchymal Transition ◽  
Paracrine Factors ◽  
Mesenchymal Transition ◽  
Multiple Tumor ◽  
Epithelium Regeneration ◽  
Intermediate Cells ◽  
Prostate Epithelium

Deregulation of androgen receptor (AR) splice variants has been implicated to play a role in prostate cancer development and progression. To understand their functions in prostate, we established a transgenic mouse model (AR3Tg) with targeted expression of the constitutively active and androgen-independent AR splice variant AR3 (a.k.a. AR-V7) in prostate epithelium. We found that overexpression of AR3 modulates expression of a number of tumor-promoting autocrine/paracrine growth factors (including Tgfβ2 and Igf1) and expands prostatic progenitor cell population, leading to development of prostatic intraepithelial neoplasia. In addition, we showed that some epithelial-mesenchymal transition-associated genes are up-regulated in AR3Tg prostates, suggesting that AR3 may antagonize AR activity and halt the differentiation process driven by AR and androgen. This notion is supported by our observations that the number of Ck5+/Ck8+ intermediate cells is increased in AR3Tg prostates after castration, and expression of AR3 transgene in these intermediate cells compromises prostate epithelium regeneration upon androgen replacement. Our results demonstrate that AR3 is a driver of prostate cancer, at least in part, through modulating multiple tumor-promoting autocrine/paracrine factors.

scholarly journals Silencing Akt1 Inhibits Starvation Induced Lung Metastasis Through Epithelial Mesenchymal Transition Independent of E-cadherin in Prostate Cancer

2020 ◽  
Author(s):  
Mei Yang ◽  
Hui Liu ◽  
Guo Ping Qiu ◽  
Fei Gao
Keyword(s):  
Prostate Cancer ◽  
Lung Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Starvation Resistance ◽  
Mesenchymal Transition ◽  
Tail Vein Injection ◽  
Emt Markers ◽  
E Cadherin

Abstract BackgroundEpithelial to mesenchymal transition (EMT) of prostate cancer (PCa) cells facilitates their progress to metastasis. We have recently reported Akt1 is an important EMT regulator, and silencing Akt1 induced EMT and inhibited the growth of PCa cells. These results imply Akt1 silencing may increase starvation resistance of PCa cells. However, little is known about the role of Akt1 of PCa cells in starvation.MethodsApoptosis was detected by TUNEL and flow cytometry, cell invasion was detected by transwells and ECIS, lung metastasis was evaluated by tail vein injection animal model, variation of EMT markers was detected by Western-blot.ResultsWe found starvation slowed down the growth and proliferation, and increased apoptosis of PCa cells; Silencing Akt1 gene inhibited these effects of starvation and decreased E-cadherin. Akt1 silencing enhanced invasion induced by starvation of PCa cells in vitro ; however, it inhibited lung metastasis induced by starvation of PCa cells in vivo unexpectedly.ConclusionStarvation or silencing Akt1 alone can promote lung metastasis of PCa cells, however, silencing Akt1 while starving PCa cells can significantly inhibit this function via EMT independent of E-cadherin.

scholarly journals Estrogen Receptors in Epithelial-Mesenchymal Transition of Prostate Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1418 ◽  
Author(s):  
Di Zazzo ◽  
Galasso ◽  
Giovannelli ◽  
Di Donato ◽  
Bilancio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Initial Response ◽  
Prostate Cancer Progression ◽  
Mesenchymal Transition ◽  
Cancer Initiation ◽  
Cancer Suppression ◽  
The Impact

Prostate cancer (PC) remains a widespread malignancy in men. Since the androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer, suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the primary intervention for this disease. Despite the initial response, prostate cancer frequently develops resistance to ADT and progresses. As such, the disease becomes metastatic and few therapeutic options are available at this stage. Although the majority of studies are focused on the role of AR signaling, compelling evidence has shown that estrogens and their receptors control prostate cancer initiation and progression through a still debated mechanism. Epithelial versus mesenchymal transition (EMT) is involved in metastatic spread as well as drug-resistance of human cancers, and many studies on the role of this process in prostate cancer progression have been reported. We discuss here the findings on the role of estrogen/estrogen receptor (ER) axis in epithelial versus mesenchymal transition of prostate cancer cells. The pending questions concerning this issue are presented, together with the impact of the available data in clinical management of prostate cancer patients.

Magnesium Chloride is an Effective Therapeutic Agent for Prostate Cancer

2018 ◽  
Vol 8 (1) ◽  
pp. 62 ◽  
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.

Prostate Carcinogenesis: Insights in relation to Epigenetics and Inflammation.

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.

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

Oncogene ◽  
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.

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

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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