Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Cancer Res. 2020 Jun 1;80(11):2125-2137. doi: 10.1158/0008-5472.CAN-19-3018. Epub 2020 Apr 7.
Peptidylarginine deiminases (PADI) catalyze posttranslational modification of many target proteins and have been suggested to play a role in carcinogenesis. Citrullination of histones by PADI4 was recently implicated in regulating embryonic stem and hematopoietic progenitor cells. Here, we investigated a possible role for PADI4 in regulating breast cancer stem cells. PADI4 activity limited the number of cancer stem cells (CSC) in multiple breast cancer models and . Mechanistically, PADI4 inhibition resulted in a widespread redistribution of histone H3, with increased accumulation around transcriptional start sites. Interestingly, epigenetic effects of PADI4 on the bulk tumor cell population did not explain the CSC phenotype. However, in sorted tumor cell populations, PADI4 downregulated expression of master transcription factors of stemness, NANOG and OCT4, specifically in the cancer stem cell compartment, by reducing the transcriptionally activating H3R17me2a histone mark at those loci; this effect was not seen in the non-stem cells. A gene signature reflecting tumor cell-autonomous PADI4 inhibition was associated with poor outcome in human breast cancer datasets, consistent with a tumor-suppressive role for PADI4 in estrogen receptor-positive tumors. These results contrast with known tumor-promoting effects of PADI4 on the tumor stroma and suggest that the balance between opposing tumor cell-autonomous and stromal effects may determine net outcome. Our findings reveal a novel role for PADI4 as a tumor suppressor in regulating breast cancer stem cells and provide insight into context-specific effects of PADI4 in epigenetic modulation. SIGNIFICANCE: These findings demonstrate a novel activity of the citrullinating enzyme PADI4 in suppressing breast cancer stem cells through epigenetic repression of stemness master transcription factors NANOG and OCT4.
肽基精氨酸脱亚氨酶（PADI）催化许多靶蛋白的翻译后修饰，并被认为在致癌作用中发挥作用。最近有研究表明，PADI4 对组蛋白的瓜氨酸化在调节胚胎干细胞和造血祖细胞中起作用。在这里，我们研究了 PADI4 在调节乳腺癌干细胞中的可能作用。PADI4 活性限制了多种乳腺癌模型中的癌症干细胞（CSC）数量，并且。从机制上讲，PADI4 抑制导致组蛋白 H3 的广泛重新分布，在转录起始位点周围积累增加。有趣的是，PADI4 对肿瘤细胞群体的表观遗传效应并不能解释 CSC 表型。然而，在分选的肿瘤细胞群体中，PADI4 通过减少这些基因座处转录激活的 H3R17me2a 组蛋白标记，下调了干性主转录因子 NANOG 和 OCT4 的表达，特别是在癌症干细胞区室中；在非干细胞中未观察到这种作用。反映肿瘤细胞自主 PADI4 抑制的基因特征与人类乳腺癌数据集的不良预后相关，这与 PADI4 在雌激素受体阳性肿瘤中的肿瘤抑制作用一致。这些结果与 PADI4 对肿瘤基质的已知促肿瘤作用形成对比，表明对立的肿瘤细胞自主和基质作用之间的平衡可能决定总体结果。我们的研究结果揭示了 PADI4 作为一种新的肿瘤抑制因子在调节乳腺癌干细胞中的作用，并深入了解了 PADI4 在表观遗传调节中的特定作用。意义：这些发现表明，瓜氨酸酶 PADI4 通过表观遗传抑制干性主转录因子 NANOG 和 OCT4，在抑制乳腺癌干细胞中发挥新的活性。
