Lapierre Marion, Linares Aurélien, Dalvai Mathieu, Duraffourd Céline, Bonnet Sandrine, Boulahtouf Abdelhay, Rodriguez Carmen, Jalaguier Stéphan, Assou Said, Orsetti Beatrice, Balaguer Patrick, Maudelonde Thierry, Blache Philippe, Bystricky Kerstin, Boulle Nathalie, Cavaillès Vincent
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
INSERM, U1194, Montpellier, France.
Oncotarget. 2016 Apr 12;7(15):19693-708. doi: 10.18632/oncotarget.7564.
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.
组蛋白赖氨酸乙酰化是一种由组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDAC）调控的表观遗传标记，在肿瘤发生中起重要作用。在本研究中，我们观察到在侵袭性最强的人类乳腺癌细胞系中（即基底样乳腺癌细胞与管腔样乳腺癌细胞相比，或恶性MCF10A乳腺癌上皮细胞系与良性MCF10A乳腺癌上皮细胞系相比），IIa类HDAC9在mRNA和蛋白质水平均有强烈的过表达。HDAC9的过表达与更高的基因转录率以及HDAC9启动子上表观遗传标记的增加有关。HDAC9在MCF7管腔样乳腺癌细胞中的异位表达导致细胞增殖增加和凋亡减少。这些效应与几种受HDAC抑制剂调控的基因（如CDKN1A、BAX和TNFRSF10A）的表达失调有关。相反，在MDA - MB436基底样乳腺癌细胞中敲低HDAC9的表达可降低细胞增殖。此外，HDAC9的高表达降低了HDAC抑制剂降低细胞增殖和调节CDKN1A基因表达的功效。有趣的是，通过全基因组转录组学方法鉴定出编码转录因子SOX9的基因是HDAC9的靶基因。在稳定转染的MCF7细胞中，SOX9沉默显著降低了HDAC9的促有丝分裂活性。最后，在一大组乳腺癌活检样本中，基底样亚型肿瘤中HDAC9的表达显著增加，与SOX9的表达相关且与预后不良有关。总之，这些结果表明HDAC9是参与乳腺癌发生和对HDAC抑制剂反应的关键因素。
