Interaction of transcription factor AP-2 gamma with proto-oncogene PELP1 promotes tumorigenesis by enhancing RET signaling.
Animals
Breast Neoplasms
/ genetics
Carcinogenesis
Cell Line, Tumor
Co-Repressor Proteins
/ genetics
Gene Expression Regulation, Neoplastic
Histones
Humans
Mice, SCID
Neoplasm Transplantation
Promoter Regions, Genetic
Proto-Oncogene Proteins c-ret
/ metabolism
Signal Transduction
Transcription Factor AP-2
/ genetics
Transcription Factors
/ genetics
PELP1
TFAP2C
breast cancer
coactivator
therapy resistance
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
revised:
10
10
2020
received:
04
07
2020
accepted:
30
11
2020
pubmed:
4
12
2020
medline:
15
1
2022
entrez:
3
12
2020
Statut:
ppublish
Résumé
A significant proportion of estrogen receptor-positive (ER+) breast cancer (BC) initially responds to endocrine therapy but eventually evolves into therapy-resistant BC. Transcription factor AP-2 gamma (TFAP2C) is a known regulator of ER activity, and high expression of TFAP2C is associated with a decreased response to endocrine therapies. PELP1 is a nuclear receptor coregulator, commonly overexpressed in BC, and its levels are correlated with poorer survival. In this study, we identified PELP1 as a novel interacting protein of TFAP2C. RNA-seq analysis of PELP1 knockdown BC cells followed by transcription factor motif prediction pointed to TFAP2C being enriched in PELP1-regulated genes. Gene set enrichment analysis (GSEA) revealed that the TFAP2C-PELP1 axis induced a subset of common genes. Reporter gene assays confirmed PELP1 functions as a coactivator of TFAP2C. Mechanistic studies showed that PELP1-mediated changes in histone methylation contributed to increased expression of the TFAP2C target gene RET. Furthermore, the TFAP2C-PELP1 axis promoted the activation of the RET signaling pathway, which contributed to downstream activation of AKT and ERK pathways in ER+ BC cells. Concomitantly, knockdown of PELP1 attenuated these effects mediated by TFAP2C. Overexpression of TFAP2C contributed to increased cell proliferation and therapy resistance in ER+ BC models, while knockdown of PELP1 mitigated these effects. Utilizing ZR75-TFAP2C xenografts with or without PELP1 knockdown, we provided genetic evidence that endogenous PELP1 is essential for TFAP2C-driven BC progression in vivo. Collectively, our studies demonstrated that PELP1 plays a critical role in TFAP2C transcriptional and tumorigenic functions in BC and blocking the PELP1-TFAP2C axis could have utility for treating therapy resistance.
Identifiants
pubmed: 33269540
doi: 10.1002/1878-0261.12871
pmc: PMC8024722
doi:
Substances chimiques
Co-Repressor Proteins
0
Histones
0
PELP1 protein, human
0
TFAP2C protein, human
0
Transcription Factor AP-2
0
Transcription Factors
0
Proto-Oncogene Proteins c-ret
EC 2.7.10.1
RET protein, human
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1146-1161Subventions
Organisme : NCI NIH HHS
ID : R01 CA179120
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178499
Pays : United States
Organisme : BLRD VA
ID : I01 BX004545
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239227
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA054174
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA257298
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA223828
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European BiochemicalSocieties.
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