JARID2 promotes stemness and cisplatin resistance in non-small cell lung cancer via upregulation of Notch1.

Increased stemness is causally linked to development of drug resistance in cancers. JARID2 is a member of the Jumonji family of proteins and regulates differentiation of embryonic stem cells. However, the role of JARID2 in lung cancer stemness and drug resistance is still unclear. In this study, we investigated the expression of JARID2 in parental and cisplatin (CDDP) resistant non-small cell lung cancer (NSCLC) cells. The function of JARID2 in modulating CDDP sensitivity of NSCLC cells was determined. It was found that JARID2 is upregulated in CDDP resistant NSCLC cells, which depends on SOX2 expression. JARID2 overexpression promotes CDDP resistance in NSCLC cells, whereas JARID2 depletion restores CDDP sensitivity in CDDP resistant NSCLC cells. Moreover, JARID2 overexpression enhances cancer stem cell-like properties in NSCLC cells, which is coupled with increased expression of cancer stem cell markers. Mechanistically, JARID2-induced stemness and CDDP resistance is mediated by upregulation of Notch1. In clinical settings, high expression of JARID2 is significantly associated with advanced TNM stage, shorter overall survival, and poor chemotherapeutic response. These findings point toward an important role of JARID2 in CDDP resistance and stemness of NSCLC and provide a promising target for overcoming CDDP resistance.