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Nuclear lamin A/C phosphorylation by loss of Androgen Receptor is a global determinant of cancer-associated fibroblast activation [ChIP-Seq2]

ABSTRACT: Alterations of nuclear structure and function, and associated impact on gene transcription, are a hallmark of cancer cells. Little is known of these alterations in Cancer-Associated Fibroblasts (CAFs), a key component of the tumor stroma. Here we show that loss of androgen receptor (AR), which triggers early steps of CAF activation in human dermal fibroblasts (HDFs), leads to nuclear membrane alterations with increased micronuclei formation and frequent ruptures, with similar alterations occurring in fully established CAFs. AR associates with nuclear lamin A/C and loss of AR results in a substantially increased lamin A/C nucleoplasmic redistribution. Mechanistically, AR functions as a bridge between lamin A/C with the protein phosphatase PPP1. In parallel with a decreased lamin-PPP1 association, AR loss results in a marked increase of lamin A/C phosphorylation at Ser 301, which is also a feature of CAFs. Phospho-Ser301 Lamin A/C binds to the transcription promoter regulatory region of multiple CAF marker genes upregulated by AR loss, and expression of a lamin A/CSer301 phosphomimetic mutant is sufficient for conversion of normal fibroblasts into tumor-promoting CAFs. The findings point to an AR - lamin A/C - PPP1 axis and lamin A/C phosphorylation at ser 301 as critical determinants of CAF activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230507 | GEO | 2024/08/06

REPOSITORIES: GEO

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Nuclear lamin A/C phosphorylation by loss of Androgen Receptor is a global determinant of cancer-associated fibroblast activation

Project description:Alterations of nuclear structure and function, and associated impact on gene transcription, are a hallmark of cancer cells. Little is known of these alterations in Cancer-Associated Fibroblasts (CAFs), a key component of the tumor stroma. Here we show that loss of androgen receptor (AR), which triggers early steps of CAF activation in human dermal fibroblasts (HDFs), leads to nuclear membrane alterations with increased micronuclei formation and frequent ruptures, with similar alterations occurring in fully established CAFs. AR associates with nuclear lamin A/C and loss of AR results in a substantially increased lamin A/C nucleoplasmic redistribution. Mechanistically, AR functions as a bridge between lamin A/C with the protein phosphatase PPP1. In parallel with a decreased lamin-PPP1 association, AR loss results in a marked increase of lamin A/C phosphorylation at Ser 301, which is also a feature of CAFs. Phospho-Ser301 Lamin A/C binds to the transcription promoter regulatory region of multiple CAF marker genes upregulated by AR loss, and expression of a lamin A/CSer301 phosphomimetic mutant is sufficient for conversion of normal fibroblasts into tumor-promoting CAFs. The findings point to an AR - lamin A/C - PPP1 axis and lamin A/C phosphorylation at ser 301 as critical determinants of CAF activation.

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Nuclear lamin A/C phosphorylation by loss of Androgen Receptor is a global determinant of cancer-associated fibroblast activation [Affymetrix]

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Nuclear lamin A/C phosphorylation by loss of Androgen Receptor is a global determinant of cancer-associated fibroblast activation [ChIP-Seq]

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Nuclear lamin A/C phosphorylation by loss of Androgen Receptor is a global determinant of cancer-associated fibroblast activation

Project description:Alterations of nuclear structure and function, and associated impact on gene transcription, are a hallmark of cancer cells. Little is known of these alterations in Cancer-Associated Fibroblasts (CAFs), a key component of the tumor stroma. Here we show that loss of androgen receptor (AR), which triggers early steps of CAF activation in human dermal fibroblasts (HDFs), leads to nuclear membrane alterations and increased micronuclei formation, which are unlinked from induction of cellular senescence. Similar alterations occur in fully established CAFs, which are overcome by restored AR function. AR associates with nuclear lamin A/C and loss of AR results in a substantially increased lamin A/C nucleoplasmic redistribution. Mechanistically, AR functions as a bridge between lamin A/C with the protein phosphatase PPP1. In parallel with a decreased lamin-PPP1 association, AR loss results in a marked increase of lamin A/C phosphorylation at Ser 301, which is also a feature of CAFs. Phosphorylated lamin A/C at Ser 301 binds to the transcription promoter regulatory region of several CAF effector genes, which are upregulated due to the loss of AR. More directly, expression of a lamin A/C Ser301 phosphomimetic mutant alone is sufficient to convert normal fibroblasts into tumor-promoting CAFs of the myofibroblast subtype, without an impact on senescence. These findings highlight the pivotal role of the AR-lamin A/C-PPP1 axis and lamin A/C phosphorylation at Ser 301 in driving CAF activation.

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Nuclear lamin A/C phosphorylation by loss of Androgen Receptor is a global determinant of cancer-associated fibroblast activation [ATAC-Seq]

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Transcriptomic analysis of CAFs with silencing of ANKRD1.

Project description:Stromal cell senescence plays a crucial role in activating cancer-associated fibroblasts (CAFs). The Androgen receptor (AR) function oversees cellular senescence and CAF activation. Here, we identify the mesenchymal-specific transcriptional coregulator ANKRD1 as a key driver of CAF conversion. ANKRD1 is strongly upregulated in CAFs and under direct negative control of AR, and its loss impairs the pro-tumorigenic potential of CAFs. ANKRD1 controls a CAF-specific gene expression program and is associated with poorer survival of HNSCC, lung, and cervical SCC patients. Mechanistically, ANKRD1 binds to the chromatin on CAF gene regulatory regions in a complex with the AP1 transcription factor family. We show that ANKRD1 enhances the AP1 DNA binding activity to CAF gene promoters. Targeting ANKRD1 with the FANA antisense oligonucleotides reverts CAFs into a normal fibroblast, disrupts AP1 complex formation, and blocks CAF’s pro-tumorigenic potential in an orthotopic model of SCC, thus representing an exciting target for stroma-oriented cancer therapy.

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Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast (CAF) activation [ChIP-seq]

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