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

Abstract

tRNA-derived fragments (tRFs) play crucial roles in cancer progression. Among them, tRF-27 has been identified as a key factor in promoting naïve trastuzumab 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.

Determinants of Chromatin Organization in Aging and Cancer—Emerging Opportunities for Epigenetic Therapies and AI Technology

“…H3K9me3High methylation is associated with poor prognosis of hepatocellular carcinomas; prevent carcinogens in normal cells [123,124]. H3K27me3 Mixed function: Reduced in breast, colorectal and nasopharyngeal cancers; elevated in B-cell lymphoma (EZH2 Y641F/N ) [108,[125][126][127]. H3K27M Hotspots mutations to the unstructured N-terminal tail of histone H3 in pediatric high-grade gliomas; lead to global reduction of H3K27me3 [128][129][130][131].…”