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Peptidylarginine Deiminase IV Regulates Breast Cancer Stem Cells via a Novel Tumor Cell-Autonomous Suppressor Role.
- Source :
-
Cancer research [Cancer Res] 2020 Jun 01; Vol. 80 (11), pp. 2125-2137. Date of Electronic Publication: 2020 Apr 07. - Publication Year :
- 2020
-
Abstract
- 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 in vitro and in vivo . 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.<br /> (©2020 American Association for Cancer Research.)
- Subjects :
- Animals
Breast Neoplasms genetics
Cell Line, Tumor
Disease Progression
Female
Gene Knockdown Techniques
Humans
Isoenzymes
MCF-7 Cells
Mice
Nanog Homeobox Protein genetics
Nanog Homeobox Protein metabolism
Octamer Transcription Factor-3 genetics
Octamer Transcription Factor-3 metabolism
Protein-Arginine Deiminase Type 4 antagonists & inhibitors
Protein-Arginine Deiminase Type 4 genetics
Transcription Factors genetics
Transcription Factors metabolism
Transcriptome
Breast Neoplasms enzymology
Breast Neoplasms pathology
Neoplastic Stem Cells enzymology
Neoplastic Stem Cells pathology
Protein-Arginine Deiminase Type 4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 80
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 32265227
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-19-3018