CLMP is a tumor suppressor that determines all-trans retinoic acid response in colorectal cancer.
Dev Cell
; 58(23): 2684-2699.e6, 2023 Dec 04.
Article
in En
| MEDLINE
| ID: mdl-37944525
ABSTRACT
CAR-like membrane protein (CLMP) is a tight junction-associated protein whose mutation is associated with congenital short bowel syndrome (CSBS), but its functions in colorectal cancer (CRC) remain unknown. Here, we demonstrate that CLMP is rarely mutated but significantly decreased in CRC patients, and its deficiency accelerates CRC tumorigenesis, growth, and resistance to all-trans retinoic acid (ATRA). Mechanistically, CLMP recruits ß-catenin to cell membrane, independent of cadherin proteins. CLMP-mediated ß-catenin translocation inactivates Wnt(Wingless and INT-1)/ß-catenin signaling, thereby suppressing CRC tumorigenesis and growth in ApcMin/+, azoxymethane/dextran sodium sulfate (AOM/DSS), and orthotopic CRC mouse models. As a direct target of Wnt/ß-catenin, cytochrome P450 hydroxylase A1 (CYP26A1)-an enzyme that degrades ATRA to a less bioactive retinoid-is upregulated by CLMP deficiency, resulting in ATRA-resistant CRC that can be reversed by administering CYP26A1 inhibitor. Collectively, our data identify the anti-CRC role of CLMP and suggest that CYP26A1 inhibitor enable to boost ATRA's therapeutic efficiency.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms
/
Beta Catenin
Limits:
Animals
/
Humans
Language:
En
Journal:
Dev Cell
Year:
2023
Document type:
Article