Enhanced MAPK signaling drives ETS1-mediated induction of miR-29b leading to downregulation of TET1 and changes in epigenetic modifications in a subset of lung SCC

• DOI: 10.1038/onc.2015.499
• Publication Date: 2016-01-18T13:16:23Z
• Authors: M A Taylor; M Wappett; O Delpuech; H Brown; C M Chresta
• Keywords: ETS1

Non-small-cell lung cancer is the leading cause of death worldwide and comprised several histological subtypes, two most common being adenocarcinoma (AC) squamous cell carcinoma (SCC). Targeted therapies have successfully improved response rates in patients with AC tumors. However, majority SCC tumors lack specific targetable mutations, making development new treatment paradigms for this disease challenging. In present study, we used iterative non-negative matrix factorization, an unbiased clustering method, on mRNA expression data from genome atlas (TCGA) a panel 24 lines to classify three segments within SCC. Analysis gene set enrichment drug sensitivity identified immune-evasion subtype that showed increased nuclear factor-κB mitogen-activated protein kinase (MAPK) inhibition, replication-stress associated ataxia telangiectasia neuroendocrine-associated phosphoinositide 3-kinase fibroblast growth factor receptor inhibition. Additionally, each these subtypes exhibited unique microRNA profile. Focusing subtype, bioinformatic analysis promoters revealed binding sites MAPK-driven ETS1 transcription factor. Indeed, found knockdown led upregulation eight microRNAs downregulation miR-29b subtype. Mechanistically, targets DNA-demethylating enzyme, TET1, resulting decreased 5-hmC epigenetic modifications. Moreover, inhibition MAPK signaling by gefitinib corresponding increase TET1 5-hmC. Collectively, our work identifies differ shows novel mechanism regulation which leads downstream changes TET1-mediated