title: Histone deacetylase 9 regulates breast cancer cell proliferation and the response to histone deacetylase inhibitors.
abstract: Histone lysine acetylation is an epigenetic mark regulated by histone acetyltransferases and histone deacetylases (HDAC) which plays an important role in tumorigenesis. In this study, we observed a strong overexpression of class IIa HDAC9, at the mRNA and protein levels, in the most aggressive human breast cancer cell lines (i.e. in basal breast cancer cells vs luminal ones or in malignant vs begnin MCF10A breast epithelial cell lines). HDAC9 overexpression was associated with higher rates of gene transcription and increased epigenetic marks on the HDAC9 promoter. Ectopic expression of HDAC9 in MCF7 luminal breast cancer cells led to an increase in cell proliferation and to a decrease in apoptosis. These effects were associated with a deregulated expression of several genes controlled by HDAC inhibitors such as CDKN1A, BAX and TNFRSF10A. Inversely, knock-down of HDAC9 expression in MDA-MB436 basal breast cancer cells reduced cell proliferation. Moreover, high HDAC9 expression decreased the efficacy of HDAC inhibitors to reduce cell proliferation and to regulate CDKN1A gene expression. Interestingly, the gene encoding the transcription factor SOX9 was identified by a global transcriptomic approach as an HDAC9 target gene. In stably transfected MCF7 cells, SOX9 silencing significantly decreased HDAC9 mitogenic activity. Finally, in a large panel of breast cancer biopsies, HDAC9 expression was significantly increased in tumors of the basal subtype, correlated with SOX9 expression and associated with poor prognosis. Altogether, these results indicate that HDAC9 is a key factor involved in mammary carcinogenesis and in the response to HDAC inhibitors.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Lapierre
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Linares
authors.affiliation: Université de Toulouse, UPS, Laboratoire de Biologie Moléculaire Eucaryote (LBME), Toulouse, France.|CNRS, UMR5099, Toulouse, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Dalvai
authors.affiliation: Laboratoire de Biologie Cellulaire, CHU Arnaud de Villeneuve, Montpellier, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Duraffourd
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Bonnet
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Abdelhay
authors.initials: A
authors.lastname: Boulahtouf
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodriguez
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Stéphan
authors.initials: S
authors.lastname: Jalaguier
authors.affiliation: Université Montpellier, Montpellier, France.|IRMB, Institute for Regenerative Medecine and Biotherapy, INSERM U1183, Montpellier, France.
authors.forename: Said
authors.initials: S
authors.lastname: Assou
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Orsetti
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.affiliation: Laboratoire de Biologie Cellulaire, CHU Arnaud de Villeneuve, Montpellier, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Maudelonde
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Blache
authors.affiliation: Université de Toulouse, UPS, Laboratoire de Biologie Moléculaire Eucaryote (LBME), Toulouse, France.|CNRS, UMR5099, Toulouse, France.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bystricky
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.|Laboratoire de Biologie Cellulaire, CHU Arnaud de Villeneuve, Montpellier, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boulle
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université Montpellier, Montpellier, France.|Institut du Cancer de Montpellier, Montpellier, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cavaillès
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C486544:HDAC9 protein, human; D006655:Histone Deacetylases
keywords: HDAC inhibitors; HDAC9; SOX9; breast cancer; histone deacetylase