Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis.
Animals
Carcinogenesis
/ genetics
Exome
/ genetics
Genotype
Haploinsufficiency
Humans
Melanocytes
/ metabolism
Melanoma
/ genetics
Mice
Mice, Nude
Mice, Transgenic
Mutation
/ radiation effects
Phosphoprotein Phosphatases
/ genetics
Proto-Oncogene Proteins B-raf
/ genetics
Tumor Cells, Cultured
Tumor Suppressor Protein p53
/ genetics
Ultraviolet Rays
/ adverse effects
BRAF
UV-induced carcinogenesis
haploinsufficiency
melanoma
protein phosphatase 6
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
revised:
10
03
2021
received:
16
10
2020
accepted:
17
03
2021
pubmed:
21
3
2021
medline:
16
6
2021
entrez:
20
3
2021
Statut:
ppublish
Résumé
According to TCGA database, mutations in PPP6C (encoding phosphatase PP6) are found in c. 10% of tumors from melanoma patients, in which they coexist with BRAF and NRAS mutations. To assess PP6 function in melanoma carcinogenesis, we generated mice in which we could specifically induce BRAF(V600E) expression and delete Ppp6c in melanocytes. In these mice, melanoma susceptibility following UVB irradiation exhibited the following pattern: Ppp6c semi-deficient (heterozygous) > Ppp6c wild-type > Ppp6c-deficient (homozygous) tumor types. Next-generation sequencing of Ppp6c heterozygous and wild-type melanoma tumors revealed that all harbored Trp53 mutations. However, Ppp6c heterozygous tumors showed a higher Signature 1 (mitotic/mitotic clock) mutation index compared with Ppp6c wild-type tumors, suggesting increased cell division. Analysis of cell lines derived from either Ppp6c heterozygous or wild-type melanoma tissues showed that both formed tumors in nude mice, but Ppp6c heterozygous tumors grew faster compared with those from the wild-type line. Ppp6c knockdown via siRNA in the Ppp6c heterozygous line promoted the accumulation of genomic damage and enhanced apoptosis relative to siRNA controls. We conclude that in the presence of BRAF(V600E) expression and UV-induced Trp53 mutation, Ppp6c haploinsufficiency promotes tumorigenesis.
Identifiants
pubmed: 33743547
doi: 10.1111/cas.14895
pmc: PMC8177767
doi:
Substances chimiques
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
Braf protein, mouse
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Phosphoprotein Phosphatases
EC 3.1.3.16
protein phosphatase 6
EC 3.1.3.16
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2233-2244Subventions
Organisme : JSPS KAKENHI
ID : 19K18757
Organisme : JSPS KAKENHI
ID : 18K16043
Organisme : JSPS KAKENHI
ID : 17K07187
Informations de copyright
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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