Cellular microRNA-127-3p suppresses oncogenic herpesvirus-induced transformation and tumorigenesis via down-regulation of SKP2
Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel le micro-ARN miR-127-3p supprime la transformation et la tumorigenèse induites par le virus de l'herpès via la réduction de l'expression de la protéine SKP2
Kaposi’s sarcoma (KS) is one of the most common cancers in sub-Saharan Africa. KS–associated herpesvirus (KSHV)-encoded miRNAs are expressed in KS and promote tumorigenesis, but the role of cellular miRNAs in KS tumorigenesis remains largely unexplored. We find that miR-127-3p is one of the most significantly down-regulated host miRNAs in KSHV-infected endothelial cells and KS patient tumors. We demonstrate that restoring miR-127-3p inhibits KSHV-induced transformation and tumorigenesis by directly targeting the oncogene SKP2 in vitro and in vivo. miR-127-3p–directed SKP2 repression increases p21Cip1 and down-regulates cyclin E/A-CDK2, resulting in RB activation and suppression of E2F- and Myc-mediated transcriptional programs. This study reveals a critical tumor-suppressive function for miR-127-3p in KS, illuminating the miR-127-3p/SKP2 axis as a promising therapeutic avenue.Kaposi’s sarcoma-associated herpesvirus (KSHV) causes the endothelial tumor KS, a leading cause of morbidity and mortality in sub-Saharan Africa. KSHV-encoded microRNAs (miRNAs) are known to play an important role in viral oncogenesis; however, the role of host miRNAs in KS tumorigenesis remains largely unknown. Here, high-throughput small-RNA sequencing of the cellular transcriptome in a KS xenograft model revealed miR-127-3p as one of the most significantly down-regulated miRNAs, which we validated in KS patient tissues. We show that restoration of miR-127-3p suppresses KSHV-driven cellular transformation and proliferation and induces G1 cell cycle arrest by directly targeting the oncogene SKP2. This miR-127-3p–induced G1 arrest is rescued by disrupting the miR-127-3p target site in SKP2 messenger RNA (mRNA) using gene editing. Mechanistically, miR-127-3p–mediated SKP2 repression elevates cyclin-dependent kinase (CDK) inhibitor p21Cip1 and down-regulates cyclin E, cyclin A, and CDK2, leading to activation of the RB protein tumor suppressor pathway and suppression of the transcriptional activities of E2F and Myc, key oncoprotein transcription factors crucial for KSHV tumorigenesis. Consequently, metabolomics analysis during miR-127-3p–induced cell cycle arrest revealed significant depletion of dNTP pools, consistent with RB-mediated repression of key dNTP biosynthesis enzymes. Furthermore, miR-127-3p reconstitution in a KS xenograft mouse model suppresses KSHV-positive tumor growth by targeting SKP2 in vivo. These findings identify a previously unrecognized tumor suppressor function for miR-127-3p in KS and demonstrate that the miR-127-3p/SKP2 axis is a viable therapeutic strategy for KS.