title: Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2.
abstract: Aberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types. However, ETS2 can act as an oncogene in some cellular backgrounds, and as a tumor suppressor in others, and the molecular mechanism responsible for this cell-type specific function remains unknown. Here, we show that ETS1 and ETS2 can regulate a cell migration gene expression program in opposite directions, and provide the first comparison of the ETS1 and ETS2 cistromes. This genomic data and an ETS1 deletion line reveal that the opposite function of ETS2 is a result of binding site competition and transcriptional attenuation due to weaker transcriptional activation by ETS2 compared to ETS1. This weaker activation was mapped to the ETS2 N-terminus and a specific interaction with the co-repressor ZMYND11 (BS69). Furthermore, ZMYND11 expression levels in patient tumors correlated with oncogenic versus tumor suppressive roles of ETS2. Therefore, these data indicate a novel and specific mechanism allowing ETS2 to switch between oncogenic and tumor suppressive functions in a cell-type specific manner.
authors.affiliation: Biology Department, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Plotnik
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hollenhorst
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011485:Protein Binding; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics* / Q000378:metabolism; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014158:Transcription, Genetic; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C494041:ETS1 protein, human; C494069:ETS2 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D050787:Proto-Oncogene Protein c-ets-2; C094763:ZMYND11 protein, human; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins