Suppression of the telomerase RNA component induces autophagy and ferroptosis in lung cancer via regulation of AMP-activated protein kinase

Abstract Objective Long non-coding RNAs (lncRNAs) are involved in tumorigenesis. The telomerase RNA component (TERC) is an lncRNA that functions as an essential template for the addition of the telomere repeat.The aims of our study were to determine the biological function and mechanism of TERC in lung adenocarcinoma. Methods RNA-seq analyses were used to compare the expression levels of TERC in cancerous and adjacent normal lung tissues. Functional assays of TERC in LUAD cell lines were performed by siRNA-mediated knockdown. Cell proliferation, migration and invasion were evaluated by WST-1 and transwell assays. Reactive oxygen species (ROS) levels were determined by flow cytometry and examined by fluorescence microscopy, and the morphology of mitochondria was observed using transmission electron microscopy. Protein expression was analyzed by western blot. The formation of autophagosomes was monitored by fluorescence microscopy following expression of fluorescent-tagged LC3. Results RNA-seq analyses show that the expression of TERC is upregulated in lung cancer tissues. Knockdown of TERC inhibits migration and invasion of LUAD cells. Mechanistic analyses indicate that silencing of TERC increases the expression of autophagy-related proteins LC3B, Beclin-1 and AMP-activated protein kinase (AMPK) meanwhile the expression of p62 protein, as well as ferroptosis-regulated proteins GPX4 and SLC7A11 were diminished. Importantly, inhibition of AMPK function counterbalances the effects of TERC knockdown on autophagy and ferroptosis in LUAD cells. Conclusions These findings reveal that suppression of TERC in lung cancer promotes autophagy and ferroptosis via regulation of AMPK. They help to understand the mechanism underlying TERC activity in tumorigenesis.