The Role of KSHV microRNAs in Bypass of Oncogene-Induced Senescence

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi’s sarcoma (KS). KSHV has the ability to bypass a host anti-proliferative defense, oncogene-induced senescence (OIS), triggered by chronic oncogene expression. KSHV encodes 18 microRNAs (miRNAs) which are thought to fine-tune host gene expression to create a local pro-tumour environment in KS tissue. However, the functions of these miRNAs remain incompletely characterized. We identified two miRNAs, miR-K5 and miR-K11 that induced bypass of senescence. Senescence bypass coincided with marked reductions in levels of the p16 tumour suppressor, a key effector of the senescence program. miRNA-induced OIS bypass also coincided with alterations in γ-H2AX and 53BP1-positive DNA damage foci. Autophagic flux is required for efficient establishment of senescence. miR-K5 and miR-K11 inhibited flux in osteosarcoma cells. These data suggest that miR-K5 and miR-K11 may suppress OIS at multiple levels, thereby contributing to the ongoing proliferation of latently KSHV-infected cells.