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| Status |
Public on Jan 11, 2021 |
| Title |
Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_1] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Peptidylarginine deiminases (PADIs) catalyze post-translational modification of many target proteins and have been suggested to play a role in carcinogenesis. Since 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. We showed by genetic and pharmacologic approaches that PADI4 activity limits the number of cancer stem cells (CSCs) in vitro and in vivo in multiple breast cancer models. A gene signature reflecting tumor cell-autonomous PADI4 inhibition is associated with poor outcome in human breast cancer datasets, consistent with a tumor suppressive role for PADI4. Mechanistically, PADI4 inhibition resulted in a global redistribution of histone H3 with 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 down-regulated expression of the master transcription factors of stemness, NANOG and POU5F1, 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. Our findings reveal a novel role for PADI4 as a tumor suppressor in regulating breast cancer stem cells, and provide insights into context-specific effects of PADI4 in epigenetic modulation.
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| Overall design |
Cells were cultured in DMEM/F12 media supplemented with 5% horse serum.
Cells were treated with PADI4 inhibitor (GSK484) or control compound (GSK107) for 72 hours.
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| Contributor(s) |
Moshkovich N, Ochoa HJ, Tang B, Yang HH, Yang Y, Huang J, Lee MP, Wakefield L |
| Citation(s) |
32265227 |
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| Submission date |
Oct 03, 2019 |
| Last update date |
Apr 12, 2021 |
| Contact name |
Maxwell Lee |
| E-mail(s) |
leemax@mail.nih.gov
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| Phone |
240-276-5239
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| Organization name |
National Cancer Institute, NIH
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| Department |
CCR
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| Lab |
Laboratory of Human Carcinogenesis
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| Street address |
Building 37, Room 5120
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (3) |
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| This SubSeries is part of SuperSeries: |
| GSE138506 |
Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells |
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| Relations |
| BioProject |
PRJNA575771 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE138415_RAW.tar |
4.0 Mb |
(http)(custom) |
TAR (of TXT) |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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