FBXW7β loss-of-function enhances FASN-mediated lipogenesis and promotes colorectal cancer growth.
Journal
Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423
Informations de publication
Date de publication:
19 05 2023
19 05 2023
Historique:
received:
06
09
2022
accepted:
28
02
2023
revised:
11
02
2023
medline:
22
5
2023
pubmed:
19
5
2023
entrez:
18
5
2023
Statut:
epublish
Résumé
Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor. FBXW7 is a highly mutated gene in CRC, but its biological functions in cancer are not fully characterized. Here, we report that FBXW7β, a FBXW7 isoform located in the cytoplasm and frequently mutated in CRC, is an E3 ligase of fatty acid synthase (FASN). Cancer-specific FBXW7β mutations that could not degrade FASN can lead to sustained lipogenesis in CRC. COP9 signalosome subunit 6 (CSN6), an oncogenic marker of CRC, increases lipogenesis via interacting with and stabilizing FASN. Mechanistic studies show that CSN6 associates with both FBXW7β and FASN, and antagonizes FBXW7β's activity by enhancing FBXW7β autoubiquitination and degradation, which in turn prevents FBXW7β-mediated FASN ubiquitination and degradation, thereby regulating lipogenesis positively. Both CSN6 and FASN are positively correlated in CRC, and CSN6-FASN axis, regulated by EGF, is responsible for poor prognosis of CRC. The EGF-CSN6-FASN axis promotes tumor growth and implies a treatment strategy of combination of orlistat and cetuximab. Patient-derived xenograft experiments prove the effectiveness of employing orlistat and cetuximab combination in suppressing tumor growth for CSN6/FASN-high CRC. Thus, CSN6-FASN axis reprograms lipogenesis to promote tumor growth and is a target for cancer intervening strategy in CRC.
Identifiants
pubmed: 37202390
doi: 10.1038/s41392-023-01405-8
pii: 10.1038/s41392-023-01405-8
pmc: PMC10195794
doi:
Substances chimiques
Cetuximab
PQX0D8J21J
Epidermal Growth Factor
62229-50-9
F-Box-WD Repeat-Containing Protein 7
0
FASN protein, human
EC 2.3.1.85
Fatty Acid Synthase, Type I
EC 2.3.1.85
Fatty Acid Synthases
EC 2.3.1.85
Orlistat
95M8R751W8
FBXW7 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
187Informations de copyright
© 2023. The Author(s).
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