ING1 Impacts Ovarian Cancer by Altering EMT
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2019-08-30
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Abstract
The INhibitor of Growth (ING) proteins are type II tumour suppressors that regulate epigenetic state and transcription by recruiting various chromatin-modifying complexes to chromatin. INGs are involved in multiple cellular processes such as DNA repair, apoptosis and cellular senescence. In this study, we investigated the potential role of ING1 in inhibiting the epithelial-mesenchymal transition (EMT) program that suppresses cancer metastasis and identifies the mechanism of how ING1 regulates gene transcription, as well as its clinical implication in epithelial ovarian cancer. Our analyses revealed that ING1 epigenetically regulates the transcription machinery of the EMT program through binding to the promoter region of Twist1, the critical gene encoding transcription factor (TF) that induce EMT. Subsequently, ING1 promoted the expression of epithelial cell markers, including E-cadherin, while suppressing the expression of mesenchymal markers such as N-cadherin. ING1 antagonized TGF-β or EGF induced EMT and inhibited cancer cell invasion and migration in a Twist1-dependent manner. Integration of ChIP-seq and RNA-seq data revealed the overall genomic binding characteristics of ING1 and its candidate target genes. Gene ontology (GO) and pathway analyses indicated that the genes targeted by ING1 were involved in diverse physiological processes and pathways, mostly associated with the EMT program. The bioinformatical analysis revealed the ING1 binding motif sequence, showing that ING1 recognized target genes through the TEAD family of transcription factors and their co-factor, YAP1, to further influence gene expression. Lastly, we found that high ING1 protein expression was associated with p16 and ARID1A levels and predicted better DSS in ovarian clear cell carcinoma (OCCC). Our data also suggested that high ING1/low N-cadherin expression predicts favourable disease-specific survival (DSS) in epithelial ovarian cancer. These data provide evidence that as a tumour suppressor, ING1 can impact ovarian cancer development through modulating the EMT process and play an essential role in regulating ovarian cancer chemoresistance. In summary, by downregulating the EMT-TF expression and hence and EMT program, ING1 suppresses tumour cell invasion and cancer metastasis. Global genomic profiling revealed new insights into ING1 biology and provided justification for further exploring ING1 functions. This study has also provided critical pre-clinical data that could help establish ING1 as a prognostic and therapeutic agent for ovarian cancer.
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Yang, Y. (2019). ING1 Impacts Ovarian Cancer by Altering EMT (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.