Reduced YAP1 and FOLR1 in gliomas predict better response to chemotherapeutics

Abstract

Gliomas harbouring mutations in IDH1 (isocitrate dehydrogenase 1) are characterized by greater sensitivity to chemotherapeutics. These mutants also exhibit diminished levels of transcriptional coactivator YAP1 (yes-associated protein 1). Enhanced DNA damage in IDH1 mutant cells, as evidenced by γH2AX formation (phosphorylation of histone variant H2A.X) and ATM (serine/threonine kinase; ataxia telangiectasia mutated) phosphorylation, was accompanied by reduced FOLR1 (folate receptor 1) expression. Diminished FOLR1, concomitant with heightened γH2AX levels, was also observed in patient-derived IDH1 mutant glioma tissues. Chromatin immunoprecipitation, overexpression of mutant YAP1, and treatment with YAP1-TEAD (TEA domain transcription factors) complex inhibitor verteporfin demonstrated regulation of FOLR1 expression by YAP1 and its partner transcription factor TEAD2. TCGA (The Cancer Genome Atlas) data analysis demonstrated better patient survival with reduced FOLR1 expression. Depletion of FOLR1 rendered IDH1 wild-type gliomas more susceptible to temozolomide-mediated death. Despite heightened DNA damage, IDH1 mutants exhibited reduced levels of IL6 (interleukin 6) and IL8 (interleukin 8) – pro-inflammatory cytokines known to be associated with persistent DNA damage. While both FOLR1 and YAP1 influenced DNA damage, only YAP1 was involved in regulating IL6 and IL8. ESTIMATE and CIBERSORTx analyses revealed the association between YAP1 expression and immune cell infiltration in gliomas. By identifying the influence of YAP1-FOLR1 link in DNA damage, our findings suggest that simultaneous depletion of both could amplify the potency of DNA damaging agents, while concomitantly reducing the release of inflammatory mediators and potentially affecting immune modulation. This study also highlights the novel role of FOLR1 as a probable prognostic marker in gliomas, predicting responsiveness to temozolomide and other DNA damaging agents.