EP300 promotes tumor stemness via epigenetic activation of CRISP3 leading to lobaplatin resistance in triple-negative breast cancer.

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
ACS Applied Electronic Materials Pub Date : 2024-09-01 Epub Date: 2024-06-16 DOI:10.1007/s13577-024-01091-w
Yan Wang, Yi Zhang, Xiaowei Qi
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Abstract

Lobaplatin shows antitumor activity against a wide range of tumors, including triple-negative breast cancer (TNBC), and has been linked to cancer stem cell pool. Here, we investigated the molecular mechanisms behind lobaplatin resistance and stemness in vitro and in vivo. Two chemoresistance-related GEO data sets (GSE70690 and GSE103115) were included to screen out relevant genes. Cysteine-rich secretory protein 3 (CRISP3) was found to be overexpressed in lobaplatin-resistant TNBC and related to poor diagnosis. CRISP3 expression was significantly correlated with tumor stemness markers in lobaplatin-resistant cells. E1A-associated protein p300 (EP300) regulated CRISP3 expression by affecting the H3K27ac modification of the CRISP3 promoter. In addition, knocking down EP300 curbed the malignant biological behavior of lobaplatin-resistant cells, which was antagonized by CRISP3 overexpression. Collectively, our results highlight the EP300/CRISP3 axis as a key driver of lobaplatin resistance in TNBC and suggest that therapeutic targeting of this axis may be an effective strategy for enhancing platinum sensitivity in TNBC.

Abstract Image

EP300通过表观遗传学激活CRISP3促进肿瘤干性,导致三阴性乳腺癌对叶铂产生耐药性。
洛铂对包括三阴性乳腺癌(TNBC)在内的多种肿瘤具有抗肿瘤活性,并与癌症干细胞池有关。在此,我们研究了体外和体内洛铂耐药性和干细胞背后的分子机制。我们纳入了两个化疗耐药性相关的GEO数据集(GSE70690和GSE103115),以筛选出相关基因。研究发现,富半胱氨酸分泌蛋白3(CRISP3)在洛铂耐药的TNBC中过表达,并与不良诊断相关。CRISP3的表达与抗叶铂细胞中的肿瘤干性标志物明显相关。E1A相关蛋白p300(EP300)通过影响CRISP3启动子的H3K27ac修饰来调控CRISP3的表达。此外,敲除EP300可抑制抗叶铂细胞的恶性生物学行为,而CRISP3的过表达可拮抗这种行为。总之,我们的研究结果突显了EP300/CRISP3轴是TNBC中叶铂耐药的关键驱动因素,并表明针对该轴的治疗可能是提高TNBC中铂敏感性的有效策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.20
自引率
4.30%
发文量
567
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