EZH2 inhibition enhances the activity of Carboplatin in aggressive-variant prostate cancer cell lines.

IF 3 4区医学 Q2 GENETICS & HEREDITY Epigenomics Pub Date : 2025-02-01 Epub Date: 2025-01-29 DOI:10.1080/17501911.2025.2453419

Maryam Latarani, Perla Pucci, Mark Eccleston, Massimiliano Manzo, Priyadarsini Gangadharannambiar, Irene Fischetti, Ilaria Alborelli, Vera Mongiardini, Namra Mahmood, Mario Paolo Colombo, Benedetto Grimaldi, Sushila Rigas, Shusuke Akamatsu, Cheryl Hawkes, Yuzhuo Wang, Elena Jachetti, Francesco Crea

{"title":"EZH2 inhibition enhances the activity of Carboplatin in aggressive-variant prostate cancer cell lines.","authors":"Maryam Latarani, Perla Pucci, Mark Eccleston, Massimiliano Manzo, Priyadarsini Gangadharannambiar, Irene Fischetti, Ilaria Alborelli, Vera Mongiardini, Namra Mahmood, Mario Paolo Colombo, Benedetto Grimaldi, Sushila Rigas, Shusuke Akamatsu, Cheryl Hawkes, Yuzhuo Wang, Elena Jachetti, Francesco Crea","doi":"10.1080/17501911.2025.2453419","DOIUrl":null,"url":null,"abstract":"Background: Aggressive Variant Prostate Cancers (AVPCs) are incurable malignancies. Platinum-based chemotherapies are used for the palliative treatment of AVPC. The Polycomb Repressive Complex 2 (PRC2) promotes prostate cancer progression via histone H3 Lysine 27 tri-methylation (H3K27me3). EZH2 encodes the catalytic subunit of PRC2. A recently developed nucleosome capture technology (Nu.QⓇ).measures H3K27me3 levels in biological fluids. EZH2 inhibitors (EZH2i) are being tested in clinical trials. We hypothesize that epigenetic reprogramming via EZH2i improves the efficacy of Carboplatin in AVPC and that EZH2i activity can be measured via both cellular- and cell-free nucleosomal H3K27me3 (cf-H3K27me3) levels.Methods: We studied the expression of PRC2 genes in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on cellular- and cf-H3K27me3 levels. We measured dose-dependent effects of Carboplatin with/without EZH2i on AVPC cell viability (IC50). We used RNA-Seq to study how EZH2i modulates gene expression in AVPC cells.Results: PRC2 genes were significantly up-regulated in AVPC vs other prostate cancer types. EZH2i reduced both cellular and cf-H3K27me3 levels. EZH2i significantly reduced Carboplatin IC50. EZH2i reduced the expression of DNA repair genes and increased the expression of p53-dependent pro-apoptotic factors.Conclusions: EZH2i plus Carboplatin is a promising combination treatment for AVPC.","PeriodicalId":11959,"journal":{"name":"Epigenomics","volume":" ","pages":"145-154"},"PeriodicalIF":3.0000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11812314/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Epigenomics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/17501911.2025.2453419","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/29 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Aggressive Variant Prostate Cancers (AVPCs) are incurable malignancies. Platinum-based chemotherapies are used for the palliative treatment of AVPC. The Polycomb Repressive Complex 2 (PRC2) promotes prostate cancer progression via histone H3 Lysine 27 tri-methylation (H3K27me3). EZH2 encodes the catalytic subunit of PRC2. A recently developed nucleosome capture technology (Nu.Q^Ⓡ).measures H3K27me3 levels in biological fluids. EZH2 inhibitors (EZH2i) are being tested in clinical trials. We hypothesize that epigenetic reprogramming via EZH2i improves the efficacy of Carboplatin in AVPC and that EZH2i activity can be measured via both cellular- and cell-free nucleosomal H3K27me3 (cf-H3K27me3) levels.

Methods: We studied the expression of PRC2 genes in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on cellular- and cf-H3K27me3 levels. We measured dose-dependent effects of Carboplatin with/without EZH2i on AVPC cell viability (IC₅₀). We used RNA-Seq to study how EZH2i modulates gene expression in AVPC cells.

Results: PRC2 genes were significantly up-regulated in AVPC vs other prostate cancer types. EZH2i reduced both cellular and cf-H3K27me3 levels. EZH2i significantly reduced Carboplatin IC₅₀. EZH2i reduced the expression of DNA repair genes and increased the expression of p53-dependent pro-apoptotic factors.

Conclusions: EZH2i plus Carboplatin is a promising combination treatment for AVPC.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

求助全文

约1分钟内获得全文去求助

来源期刊

Epigenomics GENETICS & HEREDITY-

CiteScore

5.80

自引率

2.60%

发文量

审稿时长

>12 weeks

期刊介绍： Epigenomics provides the forum to address the rapidly progressing research developments in this ever-expanding field; to report on the major challenges ahead and critical advances that are propelling the science forward. The journal delivers this information in concise, at-a-glance article formats – invaluable to a time constrained community. Substantial developments in our current knowledge and understanding of genomics and epigenetics are constantly being made, yet this field is still in its infancy. Epigenomics provides a critical overview of the latest and most significant advances as they unfold and explores their potential application in the clinical setting.