MicroRNA‐488‐3p sensitizes malignant melanoma cells to cisplatin by targeting PRKDC

Abstract

Deregulation of microRNAs (miRNAs) has been implicated in drug resistance in various types of cancers, including malignant melanoma (MM). MiR-488-3p has been reported as a tumor suppressor in several cancers. However, the exact expression patterns of miR-488-3p and the precise molecular mechanisms underlying its role in MM remain largely unknown and require further investigation. In this study, we demonstrated that miR-488-3p is significantly downregulated in MM clinical specimens and cell lines. Ectopic expression of miR-488-3p resulted in markedly increased drug sensitivity of MM cells in vitro and in vivo. The DNA-activated, catalytic polypeptide (PRKDC), which encodes DNA-dependent protein kinase catalytic subunit (DNA-PKcs), was identified as a direct target of miR-488-3p using luciferase reporter assays, qRT-PCR, and western blotting analyses. PRKDC knockdown by small interfering RNA (siRNA) alone promoted sensitivity of MM cells to cisplatin (DDP) while overexpression of PRKDC partially rescued the miR-488-3p-mediated acceleration of sensitivity to DDP in MM cells. Taken together, our results indicate that miR-488-3p serves as a drug resistance sensitizer in MM, supporting its potential as a promising therapeutic candidate.

MicroRNA‐488‐3p inhibits proliferation and induces apoptosis by targeting ZBTB2 in esophageal squamous cell carcinoma

“…Since the reverse of miR‐488‐3p effect on ESCC caused by ZBTB2 was partial, we speculated that miR‐488‐3p might have alternate target in ESCC. A previous study reported that miR‐488‐3p could target PRKDC to sensitize melanoma cells to cisplatin . PRKDC has been reported to regulate DNA damage repair, apoptosis, proliferation and cell cycle in multiple cancers, and has also been reported to relate to radioresistance in ESCC .…”

“…A number of studies have reported that miRNAs exerted antitumor functions in cancers in such manner, including in ESCC . MiR‐488‐3p has also been reported to inhibit tumor progression by targeting oncogene in glioma and melanoma . In our study, we predicted through TargetScan the potential targets for miR‐488‐3p, among which we chose ZBTB2 for further exploration.…”

“…MicroRNAs (miRNAs), as single‐strand noncoding RNAs with approximately 23 nucleotides, have been discovered to be key modulators of cancer‐related cellular biological processes including proliferation, cell cycle, apoptosis, migration, and invasion . MicroRNA‐488‐3p has been discovered to be a tumor suppressor gene in several cancers …”

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

“…mi-RNA 101 overexpression has been shown to downregulate ATM and DNA-PKcs and to sensitize tumor xenograft to IRs and pancreatic cancer cells to gemcitabine [44,45]. Another study used a mi-RNA 488-3p to sensitize in vitro malignant melanoma cells to cisplatin by targeting the PRKDC gene coding for DNA-PKcs [46]. This strategy of inhibition is still far from clinical application.…”

DNA-dependent protein kinase: Epigenetic alterations and the role in genomic stability of cancer

“…There is evidence that a single miRNA may have more than hundred mRNA targets while an individual mRNA may be targeted by multiple miRNAs [127]. Findings from a recent report demonstrated that miR-488-3p was capable of sensitizing malignant melanoma cells to cisplatin treatment by targeting transcripts synthesized from PRKDC (the gene encoding DNA-PKcs) thus leading to a decline in its protein expression levels [128]. In addition, miR-21 was shown to provoke an increase in the activity of DNA-PKcs by targeting GSK3B, thus stimulating an increase in DSBs repair leading to radioresistance observed in various tumor cell lines [129].…”