Nuclear localized p70S6K maintain cancer stem-like properties by modulating RPA3 activity in osteosarcoma.

Cancer stem-like cells (CSCs) are believed to be a pivotal contributor to therapy failure in various cancers including osteosarcoma. Targeting CSCs is a promising strategy to overcome chemoresistance and improve outcomes in osteosarcoma treatment. Besides the conventionally studied cytoplasmic p70 ribosomal protein S6 kinase (p70S6K), a well-established oncogenic driver, nuclear localized p70S6K is also observed to be related with worse prognosis in various cancers. However, there remains a considerable gap in the studies on the roles of nuclear localized p70S6K in cancer development. Here, we present a novel nuclear function of p70S6K in driving acquisition of CSC properties in osteosarcoma cells by physically interacting with replication protein A3 (RPA3), which is highly expressed in osteosarcoma CSCs subpopulation revealed by single-cell transcriptomics analyses, and modulating its single-strand DNA-binding activity. Importantly, blockage of p70S6K-RPA axis using pharmacological inhibitors remarkably suppresses the tumor growth of osteosarcoma. This study first reveals the impact and underlying mechanism of nuclear localized p70S6K and RPA3 in promoting CSCs maintenance, and highlights the nuclear p70S6K-RPA3 pathway as a promising CSC-based therapeutic target for osteosarcoma.