title: YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway.
abstract: Genetic analyses of lung cancer have helped found new treatments in this disease. We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ~20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells. Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. Taken together, our findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis.
authors.affiliation: Authors' Affiliations: Integrative Oncology, BC Cancer Research Center, Vancouver, BC, Canada; National Institutes of Health, Bethesda, Maryland; Department of Genetics, Harvard Medical School, Boston, Massachusetts; and Hamon Center of Therapeutics, University of Texas South Western, Dallas, Texas.
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Pikor
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.forename: Emily A
authors.initials: EA
authors.lastname: Vucic
authors.forename: Raj
authors.initials: R
authors.lastname: Chari
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005784:Gene Amplification; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009693:Nucleic Acid Hybridization; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C109446:YEATS4 protein, human