Histone deacetylase 9 regulates breast cancer cell proliferation and the response to histone deacetylase inhibitors
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Marion Lapierre1,2,3,4,#, Aurélien Linares1,2,3,4,#, Mathieu Dalvai5,6, Céline Duraffourd7, Sandrine Bonnet1,2,3,4, Abdelhay Boulahtouf1,2,3,4, Carmen Rodriguez1,2,3,4, Stéphan Jalaguier1,2,3,4, Said Assou3,8, Beatrice Orsetti1,2,3,4, Patrick Balaguer1,2,3,4, Thierry Maudelonde7, Philippe Blache1,2,3,4, Kerstin Bystricky5,6, Nathalie Boulle1,2,3,4,7,‡, Vincent Cavaillès1,2,3,4,‡
1IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
2INSERM, U1194, Montpellier, France
3Université Montpellier, Montpellier, France
4Institut du Cancer de Montpellier, Montpellier, France
5Université de Toulouse, UPS, Laboratoire de Biologie Moléculaire Eucaryote (LBME), Toulouse, France
6CNRS, UMR5099, Toulouse, France
7Laboratoire de Biologie Cellulaire, CHU Arnaud de Villeneuve, Montpellier, France
8IRMB, Institute for Regenerative Medecine and Biotherapy, INSERM U1183, Montpellier, France
#Should be considered as first coauthors
‡Should be considered as last coauthors
Vincent Cavaillès, e-mail: [email protected]
Keywords: breast cancer, histone deacetylase, HDAC9, HDAC inhibitors, SOX9
Received: July 27, 2015 Accepted: January 23, 2016 Published: February 22, 2016
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.
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