Investigation of the Epigenetic Regulators and Signaling Pathways influencing Pluripotency Inducing Transcription Factors mediated Tumorigenesis

摘要

Pluripotency inducing transcription factors (TFs) Oct4,Sox2 and Nanog under the influence of epigenetic modifications (especially,DNA methylation and histone H3 modifications) and signaling pathways work stringently to guard stem cell pluripotency and smoothly manoeuvre transition between differential gene expression states during both normal and pathological conditions.The present work is undertaken to investigate the influence of epigenetic regulators and signaling pathways on pluripotency inducing TFs during tumorigenesis.The expression profile of Oct4,Sox2 and Nanog in breast and prostate cancer along with epigenetic regulatory enzymes(DNA methyltransferases(DNMTs),histone methyltransferases(HMTs)and histone deacetylases(HDACs) predominantly active in controlling the expression of these TFs are studied.Furthermore,hedgehog(HH)signaling pathway mediated regulation of Oct4,Sox2 and Nanog is also examined.Oct4,Sox2 and Nanog are over-expressed both at transcript(mRNA)and protein level in a stage-specific manner in both cancers.The over-expression of Oct4,Sox2 and Nanog is associated with enhanced tumorigenic potential as is evident from reduction in cell proliferation,decrease in cell migration and invasive potential,cell cycle arrest at G1 phase and increase in apoptotic population upon silencing of these factors via si-RNA.Upon investigating the epigenetic regulatory mechanism controlling their over-expression,it was found that active histone modifications H3K4me3 and H3K9AcS10p in promoters of Oct4 and Sox2 predominantly up-regulate expression of these genes in both cancers whereas promoter DNA methylation is not effective.Alongside these marks,it is also seen that HH-Sox2 axis is active in prostate cancer and mediates androgen independent prostate cancer.As researchers and oncologists are struggling to find a successful treatment approach for metastatically aggressive malignancies,unravelling the epigenetic machinery and allied signaling pathways controlling transcriptional network of a cancer cell will be one step forward in this endeavour.