Penzo Carlotta, Arnoldo Laura, Pegoraro Silvia, Petrosino Sara, Ros Gloria, Zanin Rossella, Wiśniewski Jacek R, Manfioletti Guidalberto, Sgarra Riccardo
Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Cancers (Basel). 2019 Aug 2;11(8):1105. doi: 10.3390/cancers11081105.
Chromatin accessibility plays a critical factor in regulating gene expression in cancer cells. Several factors, including the High Mobility Group A (HMGA) family members, are known to participate directly in chromatin relaxation and transcriptional activation. The HMGA1 oncogene encodes an architectural chromatin transcription factor that alters DNA structure and interacts with transcription factors favouring their landing onto transcription regulatory sequences. Here, we provide evidence of an additional mechanism exploited by HMGA1 to modulate transcription. We demonstrate that, in a triple-negative breast cancer cellular model, HMGA1 sustains the action of epigenetic modifiers and in particular it positively influences both histone H3S10 phosphorylation by ribosomal protein S6 kinase alpha-3 (RSK2) and histone H2BK5 acetylation by CREB-binding protein (CBP). HMGA1, RSK2, and CBP control the expression of a set of genes involved in tumor progression and epithelial to mesenchymal transition. These results suggest that HMGA1 has an effect on the epigenetic status of cancer cells and that it could be exploited as a responsiveness predictor for epigenetic therapies in triple-negative breast cancers.
染色质可及性在调节癌细胞基因表达中起着关键作用。已知包括高迁移率族蛋白A（HMGA）家族成员在内的多种因素直接参与染色质松弛和转录激活。HMGA1癌基因编码一种染色质结构转录因子，该因子可改变DNA结构并与转录因子相互作用，促进其与转录调控序列结合。在此，我们提供了HMGA1用于调节转录的另一种机制的证据。我们证明，在三阴性乳腺癌细胞模型中，HMGA1维持表观遗传修饰因子的作用，特别是它对核糖体蛋白S6激酶α-3（RSK2）介导的组蛋白H3S10磷酸化和CREB结合蛋白（CBP）介导的组蛋白H2BK5乙酰化均有正向影响。HMGA1、RSK2和CBP控制一组参与肿瘤进展和上皮-间质转化的基因的表达。这些结果表明，HMGA1对癌细胞的表观遗传状态有影响，并且它可作为三阴性乳腺癌表观遗传治疗反应性的预测指标。
