Lung cancer cells expressing a shortened CDK16 3′UTR escape senescence through impaired miR‐485‐5p targeting

Abstract

Inducing senescence in cancer cells is an emerging strategy for cancer therapy. The dysregulation and mutation of genes encoding cyclin-dependent kinases (CDKs) have been implicated in various human cancers. However, whether CDK can induce cancer cell senescence remains poorly understood. We observed that CDK16 expression was high in multiple cancer types, including lung cancer, whereas various replicative senescence models displayed low CDK16 expression. CDK16 knockdown caused senescenceassociated phenotypes in lung cancer cell lines. Interestingly, the CDK16 3 0 UTR was shortened in cancer and lengthened in senescence models, which was regulated by alternative polyadenylation (APA). The longer 3 0 UTR [using the distal polyA (pA) site] generated less protein than the shorter one (using the proximal pA site). Since microRNAs (miRNAs) usually bind to the 3 0 UTR of target genes to suppress their expression, we investigated whether miRNAs targeting the region between the shortened and longer 3 0 UTR are responsible for the reduced expression. We found that miR-485-5p targeted the 3 0 UTR between the distal and proximal pA site and caused senescence-associated phenotypes by reducing protein production from the longer CDK16 transcript. Of note, CDK16 knockdown led to a reduced expression of MYC proto-oncogene, bHLH transcription factor (MYC) and CD274 molecule (PD-L1), which in turn enhanced the tumorsuppressive effects of senescent cancer cells. The present study discovered that CDK16, whose expression is under the regulation of APA and miR-485-5p, is a potential target for prosenescence therapy for lung cancer.

CircLMTK2 Silencing Attenuates Gemcitabine Resistance in Pancreatic Cancer by Sponging miR-485-5p and to Target PAK1

“…In this study, biological information analysis and experimental verification reveal that miR-485-5p bound to circLMTK2. miR-485-5p has been confirmed to play an important role in the development of cancer in previous studies [ 22 , 23 ]. However, the function role of miR-485-5p in PC is still unknown.…”

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…Thus, targeting miR-34a may improve senescence. miR-485-5p targeted CDK16 to decrease the expression of C-MYC and PD-L1, which, in turn, induced the senescence-associated phenotypes in lung cancer cell lines [ 129 ]. Therefore, CDK16 can be a target for the induction of senescence in cancer cells.…”