EHZ2 inhibition enhances the activity of platinum chemotherapy in aggressive variant prostate cancer

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-09-11 DOI:10.1101/2024.09.06.611612

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

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Abstract

Background. EZH2 promotes aggressive-variant prostate cancer (AVPC) progression via histone H3-Lysine-27 tri-methylation (H3K27me3). We hypothesize that epigenetic reprogramming via EZH2 inhibitors (EZH2i) improves the efficacy of chemotherapy in AVPC. Methods. We studied the expression of EZH2 in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on both cellular and cell free-H3K27me3 levels. We measured effects of carboplatin with/without EZH2i on AVPC cell viability (IC50). We studied how EZH2i modulate gene expression (RNA Seq). Results. EZH2 was significantly up-regulated in AVPC vs other prostate cancer types. EZH2i reduced both cellular and cell free-H3K27me3 levels. EZH2i significantly reduced carboplatin IC50. EZH2i reduced the expression of DNA repair and increased the expression of pro-apoptotic genes.

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抑制 EHZ2 可增强侵袭性变异前列腺癌的铂类化疗活性

背景。EZH2通过组蛋白H3-赖氨酸-27三甲基化（H3K27me3）促进侵袭性变异前列腺癌（AVPC）的进展。我们假设通过EZH2抑制剂（EZH2i）进行表观遗传学重编程可提高化疗对AVPC的疗效。我们研究了EZH2在临床前列腺癌队列中的表达（生物信息学）。我们测定了EZH2i对细胞和细胞游离H3K27me3水平的影响。我们测定了含/不含 EZH2i 的卡铂对 AVPC 细胞活力的影响（IC50）。我们研究了EZH2i如何调节基因表达（RNA Seq）。与其他前列腺癌类型相比，EZH2在AVPC中明显上调。EZH2i降低了细胞和细胞游离H3K27me3的水平。EZH2i能明显降低卡铂的IC50。EZH2i降低了DNA修复基因的表达，增加了促凋亡基因的表达。

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bioRxiv - Pharmacology and Toxicology

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