Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.
Translational Molecular Imaging, Max Planck Institute for Experimental Medicine, Göttingen, Germany.
Clin Epigenetics. 2022 Jan 11;14(1):7. doi: 10.1186/s13148-022-01228-4.
Basal-like breast cancer (BLBC) is one of the most aggressive malignant diseases in women with an increased metastatic behavior and poor prognosis compared to other molecular subtypes of breast cancer. Resistance to chemotherapy is the main cause of treatment failure in BLBC. Therefore, novel therapeutic strategies counteracting the gain of aggressiveness underlying therapy resistance are urgently needed. The epithelial-to-mesenchymal transition (EMT) has been established as one central process stimulating cancer cell migratory capacity but also acquisition of chemotherapy-resistant properties. In this study, we aimed to uncover epigenetic factors involved in the EMT-transcriptional program occurring in BLBC cells surviving conventional chemotherapy.
Using whole transcriptome data from a murine mammary carcinoma cell line (pG-2), we identified upregulation of Hdac4, 7 and 8 in tumor cells surviving conventional chemotherapy. Subsequent analyses of human BLBC patient datasets and cell lines established HDAC8 as the most promising factor sustaining tumor cell viability. ChIP-sequencing data analysis identified a pronounced loss of H3K27ac at regulatory regions of master transcription factors (TFs) of epithelial phenotype like Gata3, Elf5, Rora and Grhl2 upon chemotherapy. Interestingly, impairment of HDAC8 activity reverted epithelial-TFs levels. Furthermore, loss of HDAC8 activity sensitized tumor cells to chemotherapeutic treatments, even at low doses.
The current study reveals a previously unknown transcriptional repressive function of HDAC8 exerted on a panel of transcription factors involved in the maintenance of epithelial cell phenotype, thereby supporting BLBC cell survival to conventional chemotherapy. Our data establish HDAC8 as an attractive therapeutically targetable epigenetic factor to increase the efficiency of chemotherapeutics.
基底样乳腺癌（BLBC）是女性中最具侵袭性的恶性疾病之一，与其他乳腺癌分子亚型相比，其转移行为增加，预后较差。对化疗的耐药性是 BLBC 治疗失败的主要原因。因此，迫切需要新的治疗策略来对抗潜在治疗耐药性的侵袭性获得。上皮-间充质转化（EMT）已被确立为刺激癌细胞迁移能力但也获得化疗耐药性的核心过程之一。在这项研究中，我们旨在揭示 EMT-转录程序中涉及的表观遗传因素，这些因素发生在常规化疗后存活的 BLBC 细胞中。
我们使用来自鼠乳腺癌细胞系（pG-2）的全转录组数据，鉴定出在常规化疗后存活的肿瘤细胞中 Hdac4、7 和 8 的上调。对人类 BLBC 患者数据集和细胞系的后续分析确立了 HDAC8 作为维持肿瘤细胞活力的最有前途的因素。ChIP-seq 数据分析表明，在化疗后，上皮表型的主转录因子（TFs）如 Gata3、Elf5、Rora 和 Grhl2 的调控区域中，H3K27ac 明显丢失。有趣的是，HDAC8 活性的损害恢复了上皮 TF 的水平。此外，HDAC8 活性的丧失使肿瘤细胞对化疗药物更敏感，即使在低剂量下也是如此。
本研究揭示了 HDAC8 对一组参与维持上皮细胞表型的转录因子具有先前未知的转录抑制功能，从而支持 BLBC 细胞对常规化疗的存活。我们的数据确立了 HDAC8 作为一种有吸引力的治疗靶向表观遗传因子，以提高化疗的效率。
