Epigenetic modulations and lineage plasticity in advanced prostate cancer

Ge, Rongbin; Wang, Z.; Montironi, Rodolfo; Jiang, Zhong; Cheng, Monica; Santoni, Matteo; Huang, Kun; Massari, Francesco; Lü, Xin; Cimadamore, Alessia; López-Beltrán, Antonio; Liu, Cheng

doi:10.1016/j.annonc.2020.02.002

Cited by 138 publications

(94 citation statements)

References 103 publications

(125 reference statements)

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“…The occurrence and development of tumors are driven by the disorder of genetic, epigenetic, and environmental factors, and epigenetic factors play an important role as a bridge between genetic and environmental factors ( 3 , 4 ). RNA modifications are also important types of post-transcriptional epigenetic modification, and N6-methyladenosine (m6A) is the most predominant modification of mRNA.…”

Section: Introductionmentioning

confidence: 99%

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

et al. 2020

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ObjectivesRecently, an increasing number of studies have revealed that N6-methyladenosine (m6A) functions as a significant post-transcriptional modification which plays a critical role in the occurrence and progression of enriched tumors by regulating coding and non-coding RNA biogenesis. However, the biological function of m6A in breast cancer remains largely unclear.Materials and MethodsIn this study, we used a series of bioinformatic databases and tools to jointly analyze the expression of m6A methylation transferases (METTL3, METTL14, WTAP, RBM15, RBM15B and ZC3H13) and investigate the prognostic value of METTL14 and ZC3H13 in breast cancer. Besides, we analyzed the downstream carcinogenic molecular mechanisms related to METTL14 and ZC3H13 and their relationship with immune infiltration in breast tumor tissues.ResultsThe results showed that METTL14 and ZC3H13 were the down-regulated m6A methylation transferases in breast cancer. Survival outcome analysis suggested that abnormally low expression of METTL14 and ZC3H13 could predict unfavorable prognosis in four breast cancer subtypes. Moreover, their down-regulation was associated with ER-, PR- and triple-negative breast cancer patients, as well as tumor progression (increased Scarff, Bloom and Richardson grade status and Nottingham Prognostic Index classification). Co-expression analysis revealed that METTL14 and ZC3H13 had a strong positive correlation with APC, an antagonist of the Wnt signaling pathway, indicating they might cooperate in regulating proliferation, invasion, and metastasis of tumor cells. METTL14, ZC3H13, and APC expression levels had significant positive correlation with infiltrating levels of CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, and negative correlation with Treg cells in breast cancer.ConclusionsThis study demonstrated that down-regulation of METTL14 and ZC3H13 which act as two tumor suppressor genes was found in breast cancer and predicted poor prognosis. Their abnormal expression promoted breast cancer invasion by affecting pathways related to tumor progression and mediating immunosuppression.

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Section: Introductionmentioning

confidence: 99%

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

et al. 2020

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“…1A, left and right panel), this may be explained by the perspective that RNA-Seq results could just represent a snapshot of the whole process of lineage switch. Moreover, the nature of t-NEPC is a heterogeneous tumor disease that arose as a result of multiple context-dependent mechanisms, including genomic aberrations 8,31,32 , epigenetic modifications 31,33 , alternative splicing [34][35][36] , abnormal expression of transcriptional factors [11][12][13]36,37 , metabolic shifts 38 , and tumor The two-tailed Student's t test or one-way ANOVA, followed by Dunnett's t test was used to compare results between two groups with *** denoting p < 0.001. Immunoblotting assays were repeated in triplicate.…”

Section: Discussionmentioning

confidence: 99%

Loss of EHF facilitates the development of treatment-induced neuroendocrine prostate cancer

Deng

et al. 2021

Cell Death Dis

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The rising of a highly aggressive subtype of castration-resistant prostate cancer (CRPC) named treatment-induced neuroendocrine prostate cancer (t-NEPC) after androgen deprivation therapy (ADT) is well known for its features of the neuroendocrine differentiation (NED) and androgen receptor (AR) independence. However, t-NEPC is still largely unknown. Here, we found that EHF is notably depressed in t-NEPC tumors, patient-derived xenografts, transgenic mice, and cell models. Results from cell lines uncovered that ADT represses EHF expression, which is required for the ADT-induced NED. Mechanism dissection revealed that ADT decreases the EHF transcription via relieving the AR binding to different androgen-responsive elements, which then promotes the expression and enzymatic activity of enhancer of zeste homolog 2 (EZH2), consequently catalyzing tri-methylation lysine 27 of histone H3 for transcriptional repression of its downstream genes to promote the NED. Furthermore, preclinical studies from cell and mice models proved that recovery of EHF expression or using EZH2 inhibitor can attenuate aggressive properties of CRPC cells, hinder the progression of t-NEPC, and promote the response of CPRC cells to enzalutamide. Together, we elucidate that the ADT/AR/EHF/EZH2 signaling is required for the ADT-enhanced NED and plays a critical role in the progression of t-NEPC.

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“…However, these alterations are also encountered in patients with primary and advanced prostate adenocarcinoma without NEPC features [29]. NEPC may arise de novo, but often occurs in the later stages of mCRPC as a mechanism of resistance [30][31][32]. In this context, the aggressive variant prostate cancer (AVPC) is emerging as an important clinical entity that affects the outcome of patients with mCRPC [33,34].…”

Section: Discussionmentioning

confidence: 99%

Etoposide and topoisomerase II inhibition for aggressive prostate cancer: data from a translational study.

Cattrini

Capaia

Boccardo

et al. 2020

Preprint

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Background. Etoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor that demonstrated limited activity in patients with metastatic castration-resistant prostate cancer (mCRPC). In our study, we investigated the sensitivity of prostate cancer (PCa) cells (LNCaP, 22Rv1, PC3, DU145, PDB and MDB) to VP-16 and the possible relationship between VP-16 activity and TOP2 expression. We also compared the activity of VP-16 with that of docetaxel, enzalutamide and olaparib. In the datasets analysis, we explored the prevalence and clinical significance of TOP2 genetic and transcriptomic alterations in mCRPC. Methods. Cell cultures and crystal violet cell proliferation assays were performed. Specific antibodies were used in western blots analyses of cell protein extracts. Large scale datasets were analyzed in cBioportal and STRING was used for the functional enrichment analysis. Results. VP-16 was active in all PCa cell lines analyzed and this drug demonstrated increased activity in the aggressive PC3 and DU145 cells. VP-16 was more cytotoxic compared to the other treatments, except for LNCaP and 22Rv1, which were more sensitive to docetaxel. Of note, the maintainment of antiandrogen treatment in bicalutamide-resistant MDB and PDB increased sensitivity to VP-16, docetaxel and enzalutamide. Compared to LNCaP, TOP2A was found to be overexpressed in 22Rv1, DU145 and PC3, whereas TOP2B was overexpressed in 22Rv1 and PDB. In the mCRPC datasets analysis, TOP2A mRNA overexpression was associated with worse patients’ prognosis, with the molecular features of neuroendocrine prostate cancer (NEPC) and with lower androgen receptor (AR) score. Patients overexpressing TOP2A mRNA were more likely to harbor RB1 loss. Conclusions. Specific subpopulations of patients with aggressive variant prostate cancer (AVPC) could benefit from VP-16 treatment. TOP2A overexpression, rather than TOP2B, might be a good biomarker to predict response to VP-16. Further investigations are warranted to determine the role of TOP2A in mCRPC and to assess the efficacy of VP-16, alone or in combination with other agents, for the treatment of patients with mCRPC.Key points: · Etoposide is a chemotherapeutic agent that shows significant activity in preclinical models of prostate cancer and increased activity is observed in the most aggressive cells.· Overexpression of topoisomerase II alfa and decreased functionality of the androgen receptor signaling seem to be associated with response to etoposide.· Specific patients with castration-resistant prostate cancer could benefit from etoposide treatment, alone or in combination with other agents.

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Epigenetic modulations and lineage plasticity in advanced prostate cancer

Cited by 138 publications

References 103 publications

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

Loss of EHF facilitates the development of treatment-induced neuroendocrine prostate cancer

Etoposide and topoisomerase II inhibition for aggressive prostate cancer: data from a translational study.

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