title: Growth-promoting and tumourigenic activity of c-Myc is suppressed by Hhex.
abstract: c-Myc transcription factor is a key protein involved in cellular growth, proliferation and metabolism. c-Myc is one of the most frequently activated oncogenes, highlighting the need to identify intracellular molecules that interact directly with c-Myc to suppress its function. Here we show that Hhex is able to interact with the basic region/helix-loop-helix/leucine zipper of c-Myc. Knockdown of Hhex increases proliferation rate in hepatocellular carcinoma cells, whereas Hhex expression cell-autonomously reduces cell proliferation rate in multiple cell lines by increasing G1 phase length through a c-Myc-dependent mechanism. Global transcriptomic analysis shows that Hhex counter-regulates multiple c-Myc targets involved in cell proliferation and metabolism. Concomitantly, Hhex expression leads to reduced cell size, lower levels of cellular RNA, downregulation of metabolism-related genes, decreased sensitivity to methotrexate and severe reduction in the ability to form tumours in nude mouse xenografts, all indicative of decreased c-Myc activity. Our data suggest that Hhex is a novel regulator of c-Myc function that limits c-Myc activity in transformed cells.
authors.affiliation: Unidad de Hepatología Experimental, CIBERehd, Instituto de Investigación Sanitaria La Fe, Avda. Fernando Abril Martorell 106, Valencia, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Marfil
authors.affiliation: Unidad de Hepatología Experimental, CIBERehd, Instituto de Investigación Sanitaria La Fe, Avda. Fernando Abril Martorell 106, Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Blazquez
authors.affiliation: Unidad de Hepatología Experimental, CIBERehd, Instituto de Investigación Sanitaria La Fe, Avda. Fernando Abril Martorell 106, Valencia, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Serrano
authors.affiliation: Unidad de Hepatología Experimental, CIBERehd, Instituto de Investigación Sanitaria La Fe, Avda. Fernando Abril Martorell 106, Valencia, Spain.
authors.forename: J V
authors.initials: JV
authors.lastname: Castell
authors.affiliation: Unidad de Hepatología Experimental, CIBERehd, Instituto de Investigación Sanitaria La Fe, Avda. Fernando Abril Martorell 106, Valencia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Bort
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048429:Cell Size; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C078492:HHEX protein, human; C513080:Hhex protein, mouse; D018398:Homeodomain Proteins; C489427:MYC protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors