An Imbalance in Histone Modifiers Induces tRNA-Cys-GCA Overexpression and tRF-27 Accumulation by Attenuating Promoter H3K27me3 in Primary Trastuzumab-Resistant Breast Cancer.
Ningjun DuanYijia HuaXueqi YanYaozhou HeTianyu ZengJue GongZiyi FuWei LiYongmei YinPublished in: Cancers (2024)
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.
Keyphrases
- epidermal growth factor receptor
- metastatic breast cancer
- induced apoptosis
- dna methylation
- transcription factor
- positive breast cancer
- cell cycle arrest
- gene expression
- genome wide
- breast cancer cells
- poor prognosis
- tyrosine kinase
- endoplasmic reticulum stress
- risk assessment
- oxidative stress
- long non coding rna
- signaling pathway
- young adults
- squamous cell
- long noncoding rna
- human health
- heat shock
- living cells
- genome wide analysis