56P LncRNAs FENDRR, LINC02560, and SOX21-AS1 regulate chemoresistance in advanced gastric cancer

Background: Telomeric repeat-containing RNA (TERRA) is a long non-coding RNA that regulates telomere integrity, telomerase activity, and genome stability.Aberrant TERRA expression is a known feature of telomerase-positive tumors but the upstream epigenetic mechanisms controlling TERRA is unclear.FTSJ3, a nucleolar 2 -O-methyltransferase implicated in RNA modification, has recently emerged as a potential regulator of telomere biology and potential drug target. Methods:We combined epigenomic profiling, RNA-seq, telomere-specific assays, and functional loss of FTSJ3 (CRISPR knockout, RNAi) in telomerase-positive cancer models.TERRA abundance, localization, chromatin state, and telomerase activity were quantified using Northern blot, qRT-PCR, ChIP-seq, and TRAP.FTSJ3 loss and its effects on telomere stability, proliferation, DNA damage signaling, and tumorigenic potential were evaluated in vitro and in xenograft models.Results: Loss of FTSJ3 resulted in a marked increase in TERRA transcription accompanied by altered telomeric chromatin architecture and reduced telomeric RNA methylation.Elevated TERRA impaired telomerase recruitment, leading to progressive telomere dysfunction, increased DNA damage, and reduced cell viability in telomerase-dependent cancer cells.Re-expression of FTSJ3 restored appropriate TERRA regulation and telomere function, whereas methyltransferase-deficient mutants did not. Conclusions:Our findings identify FTSJ3 as a key epigenetic regulator of TERRA and an essential factor for telomerase-driven tumorigenesis.Targeting the FTSJ3-TERRA axis may represent a novel therapeutic strategy for cancers dependent on telomerase activity.