MAB21L4 Deficiency Drives Squamous Cell Carcinoma via Activation of RET.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
02 09 2022
02 09 2022
Historique:
received:
07
01
2022
revised:
02
05
2022
accepted:
10
06
2022
pubmed:
16
6
2022
medline:
9
9
2022
entrez:
15
6
2022
Statut:
ppublish
Résumé
Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. In SCC organoids and in vivo tumor models, genetic disruption of RET or selective inhibition of RET with BLU-667 (pralsetinib) suppressed SCC growth while inducing concomitant differentiation. Overall, loss of MAB21L4 early during SCC development blocks differentiation by increasing RET expression. These results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC. Downregulation of RET mediated by MAB21L4-CacyBP interaction is required to induce epidermal differentiation and suppress carcinogenesis, suggesting RET inhibition as a potential therapeutic approach in squamous cell carcinoma.
Identifiants
pubmed: 35705526
pii: 704905
doi: 10.1158/0008-5472.CAN-22-0047
pmc: PMC9444977
mid: NIHMS1818583
doi:
Substances chimiques
CACYBP protein, human
0
Calcium-Binding Proteins
0
Proto-Oncogene Proteins c-ret
EC 2.7.10.1
RET protein, human
EC 2.7.10.1
MAB21L4 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3143-3157Subventions
Organisme : Doris Duke Charitable Foundation
ID : 2018094
Pays : United States
Organisme : Doris Duke Charitable Foundation
ID : 2018094A
Pays : United States
Organisme : NIAMS NIH HHS
ID : K01 AR070895
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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