The pRb/RBL2-E2F1/4-GCN5 axis regulates cancer stem cell formation and G0 phase entry/exit by paracrine mechanisms.
Humans
Neoplastic Stem Cells
/ metabolism
Paracrine Communication
E2F1 Transcription Factor
/ metabolism
Cell Line, Tumor
Pancreatic Neoplasms
/ metabolism
E2F4 Transcription Factor
/ metabolism
Animals
Carcinoma, Pancreatic Ductal
/ pathology
Wnt Proteins
/ metabolism
Retinoblastoma Protein
/ metabolism
Breast Neoplasms
/ metabolism
p300-CBP Transcription Factors
/ metabolism
Gene Expression Regulation, Neoplastic
Proto-Oncogene Proteins p21(ras)
/ genetics
Female
Cell Proliferation
Mice
Signal Transduction
Drug Resistance, Neoplasm
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 Apr 2024
27 Apr 2024
Historique:
received:
30
12
2022
accepted:
09
04
2024
medline:
28
4
2024
pubmed:
28
4
2024
entrez:
27
4
2024
Statut:
epublish
Résumé
The lethality, chemoresistance and metastatic characteristics of cancers are associated with phenotypically plastic cancer stem cells (CSCs). How the non-cell autonomous signalling pathways and cell-autonomous transcriptional machinery orchestrate the stem cell-like characteristics of CSCs is still poorly understood. Here we use a quantitative proteomic approach for identifying secreted proteins of CSCs in pancreatic cancer. We uncover that the cell-autonomous E2F1/4-pRb/RBL2 axis balances non-cell-autonomous signalling in healthy ductal cells but becomes deregulated upon KRAS mutation. E2F1 and E2F4 induce whereas pRb/RBL2 reduce WNT ligand expression (e.g. WNT7A, WNT7B, WNT10A, WNT4) thereby regulating self-renewal, chemoresistance and invasiveness of CSCs in both PDAC and breast cancer, and fibroblast proliferation. Screening for epigenetic enzymes identifies GCN5 as a regulator of CSCs that deposits H3K9ac onto WNT promoters and enhancers. Collectively, paracrine signalling pathways are controlled by the E2F-GCN5-RB axis in diverse cancers and this could be a therapeutic target for eliminating CSCs.
Identifiants
pubmed: 38678032
doi: 10.1038/s41467-024-47680-z
pii: 10.1038/s41467-024-47680-z
doi:
Substances chimiques
E2F1 Transcription Factor
0
E2F4 Transcription Factor
0
E2F1 protein, human
0
E2F4 protein, human
0
Wnt Proteins
0
Retinoblastoma Protein
0
p300-CBP Transcription Factors
EC 2.3.1.48
WNT7B protein, human
0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
KRAS protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3580Subventions
Organisme : Pancreatic Cancer UK
ID : 2018RIF_03
Pays : United Kingdom
Informations de copyright
© 2024. The Author(s).
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