Targeting of mutant-p53 and MYC as a novel strategy to inhibit oncogenic SPAG5 activity in triple negative breast cancer.
Humans
Triple Negative Breast Neoplasms
/ genetics
Tumor Suppressor Protein p53
/ metabolism
Proto-Oncogene Proteins c-myc
/ metabolism
Cell Line, Tumor
Female
Cell Cycle Proteins
/ metabolism
Gene Expression Regulation, Neoplastic
Animals
Transcription Factors
/ metabolism
Adaptor Proteins, Signal Transducing
/ metabolism
Mutation
/ genetics
Mice
YAP-Signaling Proteins
/ metabolism
Mice, Nude
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
20 Aug 2024
20 Aug 2024
Historique:
received:
08
03
2024
accepted:
07
08
2024
revised:
02
08
2024
medline:
21
8
2024
pubmed:
21
8
2024
entrez:
20
8
2024
Statut:
epublish
Résumé
Triple negative breast cancer (TNBC) is an aggressive disease which currently has no effective therapeutic targets and prominent biomarkers. The Sperm Associated antigen 5 (SPAG5) is a mitotic spindle associated protein with oncogenic function in several human cancers. In TNBC, increased SPAG5 expression has been associated with tumor progression, chemoresistance, relapse, and poor clinical outcome. Here we show that high SPAG5 expression in TNBC is regulated by coordinated activity of YAP, mutant p53 and MYC. Depletion of YAP or mutant p53 proteins reduced SPAG5 expression and the recruitment of MYC onto SPAG5 promoter. Targeting of MYC also reduced SPAG5 expression and concomitantly tumorigenicity of TNBC cells. These effects of MYC targeting were synergized with cytotoxic chemotherapy and markedly reduced TNBC oncogenicity in SPAG5-expression dependent manner. These results suggest that mutant p53-MYC-SPAG5 expression can be considered as bona fide predictors of patient's outcome, and reliable biomarkers for effective anticancer therapies.
Identifiants
pubmed: 39164278
doi: 10.1038/s41419-024-06987-x
pii: 10.1038/s41419-024-06987-x
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
Proto-Oncogene Proteins c-myc
0
SPAG5 protein, human
0
Cell Cycle Proteins
0
Transcription Factors
0
MYC protein, human
0
Adaptor Proteins, Signal Transducing
0
TP53 protein, human
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
603Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : 22759
Informations de copyright
© 2024. The Author(s).
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