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.
Highlights
Despite real improvement in patient treatment, breast cancer remains a significant global health issue and a major cause of cancer death worldwide [1]
By comparing histone deacetylases (HDAC) expression at the mRNA level in a panel of human breast tumor cell lines classified as luminal, basal A and basal B [13, 14], we found the level of HDAC9 expression to be strikingly increased in basal cells as compared to luminal cells (p = 0.0059) (Figure 1A)
Comparison of mRNA levels for total HDAC9 with those of the longest HDAC9 isoforms and the MITR isoform lacking the catalytic deacetylase domain showed a similar pattern of distribution among luminal, basal A and basal B cells (Supplementary Figure 2)
Summary
Despite real improvement in patient treatment, breast cancer remains a significant global health issue and a major cause of cancer death worldwide [1]. Breast cancer is a complex and heterogeneous disease and at least five distinct molecular subtypes differing in clinical outcomes and treatment responses have been identified www.impactjournals.com/oncotarget based on gene expression profiles [2]. Breast cancers are classified according to different parameters including stage, grade and expression of molecular targets such as estrogen, progesterone and human epidermal growth factor receptors. A number of epigenetic aberrations have been characterized in breast cancer, including DNA methylation and various histone modifications, such as methylation, phosphorylation, ubiquitination, sumoylation and acetylation [4]. Acetylation is controlled by a balance in activity between histone acetyltransferase and histone deacetylase (HDAC). Human HDACs form a large family of 18 members classified in four groups (I to IV) based on sequence homologies [5, 6]
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