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Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138506 | GEO | 2021/01/11

REPOSITORIES: GEO

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Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [Array]

Project description: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.

2021-01-11 | GSE138407 | GEO

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [ChIP-Seq]

2021-01-11 | GSE138505 | GEO

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_1]

2021-01-11 | GSE138415 | GEO

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_2]

2021-01-11 | GSE143442 | GEO

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

Project description: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.

| S-EPMC8294167 | biostudies-literature

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells

Project description:Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells

| PRJNA576212 | ENA

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [Array]

Project description:Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [Array]

| PRJNA575748 | ENA

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_1]

Project description:Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_1]

| PRJNA575771 | ENA

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_2]

Project description:Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_2]

| PRJNA600506 | ENA

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [ChIP-Seq]

Project description:Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [ChIP-Seq]

| PRJNA576214 | ENA

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