Reduced YAP1 and FOLR1 in gliomas predict better response to chemotherapeutics

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 (yesassociated protein 1). Enhanced DNA damage in IDH1 mutant cells, as evidenced by & gamma;H2AX 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 & gamma;H2AX 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.

Automated summary

Gliomas with IDH1 mutations are more sensitive to chemotherapy and have lower levels of YAP1. These mutations lead to enhanced DNA damage and reduced FOLR1 expression. Similar observations were made in patient-derived IDH1 mutant glioma tissues. YAP1 and its partner TEAD2 were found to regulate FOLR1 expression. Reduced FOLR1 expression was associated with better patient survival. Depletion of FOLR1 increased the susceptibility of IDH1 wild-type gliomas to temozolomide-induced cell death. IDH1 mutants exhibited reduced levels of pro-inflammatory cytokines IL6 and IL8. YAP1 influenced DNA damage and the regulation of IL6 and IL8. YAP1 expression was associated with immune cell infiltration in gliomas. Simultaneous depletion of YAP1 and FOLR1 could enhance the potency of DNA damaging agents and reduce the release of inflammatory mediators, potentially affecting immune modulation. FOLR1 was identified as a potential prognostic marker for gliomas, predicting responsiveness to temozolomide and other DNA damaging agents.