Uncontrolled overactivation of autophagy may lead to autophagic cell death, suppression of which is a pro-survival strategy for tumors.,However, mechanisms involving key regulators in modulating autophagic cell death remain poorly defined.,Here, we report a novel long noncoding RNA, p53 upregulated regulator of p53 levels (PURPL), functions as an oncogene to promote cell proliferation, colony formation, migration, invasiveness, and inhibits cell death in melanoma cells.,Mechanistic studies showed that PURPL promoted mTOR-mediated ULK1 phosphorylation at Ser757 by physical interacting with mTOR and ULK1 to constrain autophagic response to avoid cell death.,Loss of PURPL led to AMPK-mediated phosphorylation of ULK1 at Ser555 and Ser317 to over-activate autophagy and induce autophagic cell death.,Our results identify PURPL as a key regulator to modulate the activity of autophagy initiation factor ULK1 to repress autophagic cell death in melanoma and may represent a potential intervention target for melanoma therapy.
Cutaneous malignant melanoma (CMM) is responsible for ≥1/2 of skin cancer-related mortalities.,The aberrant expression of long non-coding RNAs (lncRNAs) has been associated with the development of CMM.,However, to the best of our knowledge, the role of the lncRNA TINCR ubiquitin domain containing (TINCR) in CMM has not been previously investigated, and thus, the current study aimed to evaluate this in vitro and in vivo.,Reverse transcription-quantitative PCR (RT-qPCR) was used to analyze microRNA (miR)-424-5p expression, and RT-qPCR and western blotting were used to measure TINCR, large tumor suppressor kinase 1 (LATS1), cellular communication network factor 2 (CTGF), cellular communication network factor 1 (CCN1) and AXL receptor tyrosine kinase (AXL) mRNA and protein expression levels, respectively.,Cell Counting Kit-8, flow cytometry and Transwell assays were used to detect the proliferation, apoptosis and invasion of CMM cell lines, respectively.,The binding sites between TINCR and miR-424-5p were predicted using the miRDB database.,A dual luciferase reporter assay and RT-qPCR were used to identify the relationship between TINCR and miR-424-5p in CMM cell lines.,The bioinformatics analysis revealed that TINCR was one of the most significantly downregulated lncRNAs in CMM, and advanced stage CMM tissues showed the greatest decrease in TINCR expression.,Moreover, in the collected CMM tissues and tested cell lines of the current study, TINCR expression was found to be downregulated compared with the respective controls.,Notably, TINCR overexpression inhibited the expression levels of CTGF, CCN1 and AXL, decreased the proliferation and invasion, and induced the apoptosis of CMM cell lines.,In addition, a mutual binding association was identified between miR-424-5p and TINCR in CMM cells.,LATS1, a target of miR-424-5p, was found to be positively regulated by TINCR.,TINCR activated Hippo signaling and repressed the activity of Yes 1 associated transcriptional regulator by regulating LATS1 expression, while LATS1 knockdown reversed the effect of TINCR overexpression on CMM cells.,Collectively, the findings of the present study suggested that TINCR may attenuate the progression of CMM by regulating the miR-424-5p/LATS1 signaling axis.,These results indicated that TINCR may play a tumor suppressive role in CMM.