文章：

在原发性曲妥珠单抗耐药乳腺癌中，组蛋白修饰失衡通过减弱启动子H3K27me3水平，诱导tRNA-Cys-GCA过表达及tRF-27积累

An Imbalance in Histone Modifiers Induces tRNA-Cys-GCA Overexpression and tRF-27 Accumulation by Attenuating Promoter H3K27me3 in Primary Trastuzumab-Resistant Breast Cancer

原文发布日期：11 March 2024

DOI: 10.3390/cancers16061118

类型: Article

开放获取: 是

英文摘要：

tRNA-derived fragments (tRFs) play crucial roles in cancer progression. Among them, tRF-27 has been identified as a key factor in promotingnaïvetrastuzumab resistance in HER2-positive breast cancer. However, the origin of tRF-27 remains uncertain. In this study, we propose that the upregulated expression of specific cysteine tRNAs may lead to the increased accumulation of tRF-27 in trastuzumab-resistant JIMT1 cells. Mechanistically, the reduced inhibitory H3K27me3 modification at the promoter regions of tRF-27-related tRNA genes in JIMT1 cells, potentially resulting from decreased EZH2 and increased KDM6A activity, may be a critical factor stimulating the transcriptional activity of these tRNA genes. Our research offers fresh insights into the mechanisms underlying elevated tRF-27 levels in trastuzumab-resistant breast cancer cells and suggests potential strategies to mitigate trastuzumab resistance in clinical treatments.

摘要翻译： 

tRNA来源片段（tRFs）在癌症进展中发挥关键作用。其中，tRF-27已被证实是促进HER2阳性乳腺癌对曲妥珠单抗产生原发性耐药的关键因子。然而，tRF-27的具体来源尚不明确。本研究提出，特定半胱氨酸tRNA的表达上调可能导致tRF-27在耐药性JIMT1细胞中异常积累。机制研究表明，JIMT1细胞中tRF-27相关tRNA基因启动子区域的抑制性组蛋白修饰H3K27me3水平降低——这可能是由EZH2活性下降和KDM6A活性升高共同导致——可能成为激活这些tRNA基因转录活性的关键因素。本研究为阐明曲妥珠单抗耐药乳腺癌细胞中tRF-27水平升高的机制提供了新视角，并为临床治疗中克服曲妥珠单抗耐药提供了潜在策略。

原文链接：

An Imbalance in Histone Modifiers Induces tRNA-Cys-GCA Overexpression and tRF-27 Accumulation by Attenuating Promoter H3K27me3 in Primary Trastuzumab-Resistant Breast Cancer