title: Interplay between chromatin-modifying enzymes controls colon cancer progression through Wnt signaling.
abstract: Cancer progression is associated with epigenetic alterations, such as changes in DNA methylation, histone modifications or variants incorporation. The p400 ATPase, which can incorporate the H2A.Z variant, and the Tip60 histone acetyltransferase are interacting chromatin-modifying proteins crucial for the control of cell proliferation. We demonstrate here that Tip60 acts as a tumor suppressor in colon, since mice heterozygous for Tip60 are more susceptible to chemically induced preneoplastic lesions and adenomas. Strikingly, heterozygosity for p400 reverses the Tip60-dependent formation of preneoplastic lesions, uncovering for the first time pro-oncogenic functions for p400. By genome-wide analysis and using a specific inhibitor in vivo, we demonstrated that these effects are dependent on Wnt signaling which is antagonistically impacted by p400 and Tip60: p400 directly favors the expression of a subset of Wnt-target genes and regulators, whereas Tip60 prevents β-catenin acetylation and activation. Taken together, our data underline the physiopathological importance of interplays between chromatin-modifying enzymes in the control of cancer-related signaling pathways.
authors.affiliation: Université de Toulouse, UPS, F-31062 Toulouse, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Chevillard-Briet
authors.forename: Muriel
authors.initials: M
authors.lastname: Quaranta
authors.forename: Aude
authors.initials: A
authors.lastname: Grézy
authors.forename: Lise
authors.initials: L
authors.lastname: Mattera
authors.forename: Céline
authors.initials: C
authors.lastname: Courilleau
authors.forename: Magali
authors.initials: M
authors.lastname: Philippe
authors.forename: Pascale
authors.initials: P
authors.lastname: Mercier
authors.forename: Denis
authors.initials: D
authors.lastname: Corpet
authors.forename: John
authors.initials: J
authors.lastname: Lough
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.forename: Rikiro
authors.initials: R
authors.lastname: Fukunaga
authors.forename: Didier
authors.initials: D
authors.lastname: Trouche
authors.forename: Fabrice
authors.initials: F
authors.lastname: Escaffit
mesh_terms: D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D051548:Histone Acetyltransferases / Q000378:metabolism / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology*; D000074443:Lysine Acetyltransferase 5; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D053496:Inositol 1,4,5-Trisphosphate Receptors; C025389:Itpr1 protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5