miR-92a-3p and MYCBP2 are involved in MS-275-induced and c-myc-mediated TRAIL-sensitivity in melanoma cells

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• The c-myc oncogene's role in tumors is context-dependent, acting as either an oncogene or proapoptotic factor.
• Histone deacetylase inhibitors like MS-275 can sensitize melanoma cells to TRAIL-induced apoptosis via c-FLIP repression.
• The miR-17-92 cluster, including miR-92a-3p, is implicated in apoptosis and cancer progression.

Purpose of the Study:

• To investigate if MS-275 enhances melanoma cell death by regulating apoptosis-associated microRNAs, specifically the miR-17-92 cluster.
• To elucidate the role of miR-92a-3p and its target gene MYCBP2 in MS-275-mediated sensitization to TRAIL-induced apoptosis in melanoma.

Main Methods:

• Treatment of melanoma cells (cutaneous and uveal, TRAIL-resistant and -sensitive) with MS-275.
• Analysis of miR-92a-3p expression levels post-treatment.
• Bioinformatic prediction and experimental validation of miR-92a-3p targets (MYCBP2).
• Gain- and loss-of-function studies for miR-92a-3p and MYCBP2.
• Assessment of apoptosis, c-myc, and c-FLIP expression.

Main Results:

• MS-275 treatment decreased miR-92a-3p expression in all tested melanoma cells.
• MYCBP2 was identified and validated as a direct target of miR-92a-3p.
• Downregulation of MYCBP2 mimicked the pro-apoptotic effects of miR-92a-3p reduction and prevented c-FLIP repression.
• Silencing MYCBP2 counteracted the pro-apoptotic effects of miR-92a-3p downregulation and c-myc-induced c-FLIP repression.

Conclusions:

• MS-275 triggers downregulation of oncogenic miR-92a-3p, leading to MYCBP2 overexpression.
• MYCBP2 acts as a mediator for miR-92a-3p and c-myc functions in apoptosis.
• This study reveals a novel post-transcriptional epigenetic mechanism of MS-275 in enhancing melanoma cell susceptibility to TRAIL-induced apoptosis.