CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo.
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
21
09
2020
accepted:
10
12
2020
revised:
09
12
2020
pubmed:
9
1
2021
medline:
5
4
2022
entrez:
8
1
2021
Statut:
ppublish
Résumé
The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly contributes to metastasis formation in vivo. By considering >6800 patients we found that the CHD1 deletion negatively influences metastasis-free survival in R0 patients (HR: 2.32; 95% CI: 1.61, 3.33; p < 0.001) independent of preoperative PSA, pT stage, pN status, Gleason Score, and BCR. Moreover, CHD1 deletion predicts shortened BCR-free survival in pT2 patients and cancer-specific survival in all patients. In vivo, CHD1 loss increases spontaneous pulmonary metastasis formation in two distinct PCa models coupled with a higher number of multicellular colonies as compared to single-cell metastases. Transcriptome analyses revealed down-regulation of the PCa-specific metastasis suppressor and TGFβ signaling regulator PMEPA1 after CHD1 depletion in both tested PCa models. CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo.
Identifiants
pubmed: 33414516
doi: 10.1038/s41417-020-00288-z
pii: 10.1038/s41417-020-00288-z
pmc: PMC8761572
doi:
Substances chimiques
DNA-Binding Proteins
0
Membrane Proteins
0
PMEPA1 protein, human
0
Prostate-Specific Antigen
EC 3.4.21.77
DNA Helicases
EC 3.6.4.-
CHD1 protein, human
EC 3.6.4.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
49-61Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : LA3373/8-1
Informations de copyright
© 2021. The Author(s).
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