Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.
Cell Death Dis. 2021 Nov 29;12(12):1118. doi: 10.1038/s41419-021-04407-y.
Breast cancer (BC) is the most common cancer occurring in women but also rarely develops in men. Recent advances in early diagnosis and development of targeted therapies have greatly improved the survival rate of BC patients. However, the basal-like BC subtype (BLBC), largely overlapping with the triple-negative BC subtype (TNBC), lacks such drug targets and conventional cytotoxic chemotherapies often remain the only treatment option. Thus, the development of resistance to cytotoxic therapies has fatal consequences. To assess the involvement of epigenetic mechanisms and their therapeutic potential increasing cytotoxic drug efficiency, we combined high-throughput RNA- and ChIP-sequencing analyses in BLBC cells. Tumor cells surviving chemotherapy upregulated transcriptional programs of epithelial-to-mesenchymal transition (EMT) and stemness. To our surprise, the same cells showed a pronounced reduction of polycomb repressive complex 2 (PRC2) activity via downregulation of its subunits Ezh2, Suz12, Rbbp7 and Mtf2. Mechanistically, loss of PRC2 activity leads to the de-repression of a set of genes through an epigenetic switch from repressive H3K27me3 to activating H3K27ac mark at regulatory regions. We identified Nfatc1 as an upregulated gene upon loss of PRC2 activity and directly implicated in the transcriptional changes happening upon survival to chemotherapy. Blocking NFATc1 activation reduced epithelial-to-mesenchymal transition, aggressiveness, and therapy resistance of BLBC cells. Our data demonstrate a previously unknown function of PRC2 maintaining low Nfatc1 expression levels and thereby repressing aggressiveness and therapy resistance in BLBC.
乳腺癌（BC）是女性中最常见的癌症，但也很少发生在男性中。早期诊断和靶向治疗的最新进展极大地提高了 BC 患者的生存率。然而，基底样乳腺癌亚型（BLBC），在很大程度上与三阴性乳腺癌亚型（TNBC）重叠，缺乏这样的药物靶点，传统的细胞毒性化疗通常仍然是唯一的治疗选择。因此，对细胞毒性治疗的耐药性发展具有致命的后果。为了评估表观遗传机制的参与及其通过提高细胞毒性药物效率的治疗潜力，我们在 BLBC 细胞中结合了高通量 RNA 和 ChIP-seq 分析。化疗后存活的肿瘤细胞上调了上皮间质转化（EMT）和干性的转录程序。令我们惊讶的是，相同的细胞表现出多梳抑制复合物 2（PRC2）活性的明显降低，其亚基 Ezh2、Suz12、Rbbp7 和 Mtf2 的下调。从机制上讲，PRC2 活性的丧失导致通过从抑制性 H3K27me3 到调节区域的激活性 H3K27ac 标记的表观遗传开关，一组基因的去抑制。我们确定 NFATc1 是 PRC2 活性丧失后上调的基因之一，并且直接参与了化疗后存活时发生的转录变化。阻断 NFATc1 的激活减少了 BLBC 细胞的上皮间质转化、侵袭性和耐药性。我们的数据表明 PRC2 以前未知的功能是维持低 NFATc1 表达水平，从而抑制 BLBC 的侵袭性和耐药性。
