The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/[beta]-catenin to RTK/MAPK signaling

Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here, we report that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch o...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2024-03, Vol.134 (6)
Main Authors: Madan, Babita, Wadia, Shawn R, Patnaik, Siddhi, Harmston, Nathan, Tan, Emile, Tan, Iain Bee Huat, Nes, W. David, Petretto, Enrico, Virshup, David M
Format: Article
Language:English
Subjects:
Amino acids
Analysis
Cell differentiation
Cell proliferation
Cell research
Cholesterol
Colorectal cancer
Fatty acids
Genetic aspects
Health aspects
Lipids
Oxidases
Physiological aspects
Protein kinases
Synthesis
Wnt proteins
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here, we report that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulated the abundance of the specific C4-methyl sterols lophenol and dihydro-T-MAS. Highlighting its clinical relevance, FAXDC2 was repressed in Wnt/[beta]-catenin-high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulated in the cancerous tissues and not in adjacent normal tissues. FAXDC2 linked Wnts to RTK/MAPK signaling. Wnt inhibition drove increased recycling of RTKs and activation of the MAPK pathway, and this required FAXDC2. Blocking Wnt signaling in Wnt-high cancers caused both differentiation and senescence; and this was prevented by knockout of FAXDC2. Our data show the integration of 3 ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation.
ISSN:0021-9738
DOI:10.1172/JCI171222.