PARP1-stabilized FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/β-catenin signalling pathway

Abstract

Abstract Background: Ovarian cancer (OC) is one of the most common fatal malignancies in females worldwide. Only a few articles have reported that Forkhead box Q1 (FOXQ1) is elevated in OC tissues and associated with prognosis, but its cancer-promoting mechanism has not been clarified. Methods: We analysed the relationship between FOXQ1 expression and clinical prognosis through analyses of public databases and data from our own centre. Subsequently, the carcinogenic effect of FOXQ1 was demonstrated by phenotypic experiments in vitro and in vivo. Mechanistically, downstream transcriptional regulatory molecules and signalling pathways were identified by RNA-seq, ChIP-seq, KEGG and GSEA, and promoter binding sites were identified by luciferase reporter gene assay. The upstream regulatory relationship is explored through Co-IP, immunofluorescence (IF), mass spectrum (MS) and ubiquitination experiments. Finally, this pathway was verified by small animal drug experiments and the relationship between clinical specimens and prognosis. Results: Here, we show that FOXQ1 is overexpressed in OC and clinically associated with metastasis and patient prognosis. FOXQ1 significantly promotes OC cell proliferation and metastasis in vitro and in vivo. Mechanistically, FOXQ1 can promote LAMB3 transcription by binding to its promoter region. The oncogenic effects of FOXQ1 are mediated by theLAMB3/WNT/β-catenin pathway. Moreover, PARP1 can inhibit the ubiquitination-mediateddegradation of FOXQ1 by targeting the E3 ubiquitin ligase CHIP. Finally, the role of PARP1/FOXQ1/LAMB3/WNT/β-catenin pathway in OC was demonstrated through drug combination experiments in animals and clinical prognosis. Conclusions: Taken together, our data indicate that FOXQ1, stabilized by PARP1, can promote the progression of OC through the LAMB3/WNT/β-catenin pathway.