Peptidylarginine Deiminase IV Regulates Breast Cancer Stem Cells via a Novel Tumor Cell-Autonomous Suppressor Role.

Peptidylarginine deiminases catalyze posttranslational modification of many target proteins and have been suggested to play a role in carcinogenesis. Citrullination of histones by was recently implicated in regulating embryonic stem and hematopoietic progenitor cells. Here, we investigated a possible role for duanyu1563I4 in regulating breast cancer stem cells. duanyu1563I4 activity limited the number of cancer stem cells (CSC) in multiple breast cancer models in vitro and in vivo. Mechanistically, duanyu1563I4 inhibition resulted in a widespread redistribution of histone H3, with increased accumulation around transcriptional start sites. Interestingly, epigenetic effects of duanyu1563I4 on the bulk tumor cell population did not explain the CSC phenotype. However, in sorted tumor cell populations, duanyu1563I4 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 duanyu1563I4 inhibition was associated with poor outcome in human breast cancer datasets, consistent with a tumor-suppressive role for duanyu1563I4 in estrogen receptor-positive tumors. These results contrast with known tumor-promoting effects of duanyu1563I4 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 duanyu1563I4 as a tumor suppressor in regulating breast cancer stem cells and provide insight into context-specific effects of duanyu1563I4 in epigenetic modulation. SIGNIFICANCE: These findings demonstrate a novel activity of the citrullinating enzyme duanyu1563I4 in suppressing breast cancer stem cells through epigenetic repression of stemness master transcription factors NANOG and OCT4.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}