The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling
Babita Madan, … , Enrico Petretto, David M. Virshup
Babita Madan, … , Enrico Petretto, David M. Virshup
Published January 23, 2024
Citation Information: J Clin Invest. 2024;134(6):e171222. https://doi.org/10.1172/JCI171222.
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Research Article Metabolism Oncology

The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling

Abstract

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/β-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.

Authors

Babita Madan, Shawn R. Wadia, Siddhi Patnaik, Nathan Harmston, Emile Tan, Iain Bee Huat Tan, W. David Nes, Enrico Petretto, David M. Virshup

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Figure 3

FAXDC2 expression correlates with and drives changes in C4-methyl sterols.

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FAXDC2 expression correlates with and drives changes in C4-methyl stero...
(A–C) Primary Wnt-high colorectal cancers have repressed FAXDC2 expression and high levels of lophenol. (A) FAXDC2 is repressed in primary colorectal cancers compared with corresponding normal tissues. Expression of FAXDC2 was compared in normal tissues versus tumor tissues using GEPIA 2.0 (TCGA and GTEx data sets). (B) H3K4me3, a marker of active transcription, marks the FAXDC2 genomic locus in the normal colon but is absent in cancer cell lines. Data from Cistrome Data Browser. (C) Lophenol is markedly elevated in primary colorectal cancers. Sterol abundance was measured in primary colorectal cancers and adjacent normal tissue by GC-MS. Each point represents lophenol levels in an individual tumor, n = 12 tumors per group. (D–H) Manipulation of FAXDC2 expression regulates C4-methyl sterol abundance. (D) Relative expression of FAXDC2 in HPAF-II, FAXDC2-KO, and FAXDC2-OE xenografts as measured by qRT-PCR. (E and F) Knockout of FAXDC2 abrogates the ETC-159 treatment–induced change in the abundance of C4-methyl sterols. Sterol abundance was measured in HPAF-II and FAXDC2-KO xenografts from control and ETC-159–treated mice. Each point represents the level of indicated methyl sterols measured using GC-MS in an individual tumor sample, n = 4–5 per group. (G and H) FAXDC2 overexpression reduces lophenol and T-MAS to levels comparable to those in the Wnt-inhibited tumors. Sterol abundance was measured in HPAF-II and FAXDC2-OE xenografts from control and ETC-159–treated mice. Each point represents the abundance of methyl sterols measured using GC-MS in an individual tumor sample, n = 4–5 per group. P values were calculated by Mann-Whitney U test for all graphs in this figure. ***P ≤ 0.001.