Abstract
Dysregulated fatty acid metabolism is an attractive therapeutic target for colorectal cancer (CRC). We previously reported that fatty acid synthase (FASN), a key enzyme of de novo synthesis, promotes the initiation and progression of CRC. However, the mechanisms of how upregulation of FASN promotes the initiation and progression of CRC are not completely understood. Here, using Apc/VillinCre and ApcMin mouse models, we show that upregulation of FASN is associated with an increase in activity of β-catenin and expression of multiple stem cell markers, including Notum. Genetic and pharmacological downregulation of FASN in mouse adenoma organoids decreases the activation of β-catenin and expression of Notum and significantly inhibits organoid formation and growth. Consistently, we demonstrate that NOTUM is highly expressed in human CRC and its ex- pression positively correlates with the expression of FASN in tumor tissues. Utilizing overexpression and shRNA-mediated knockdown of FASN, we demonstrate that upregulation of FASN increases β-catenin transcriptional activity, NOTUM expression and secretion, and enhances stem-like prop- erties of human CRC cells. Pharmacological inhibition of NOTUM decreases adenoma organoids growth and proliferation of cancer cells. In summary, upregulation of FASN enhances β-catenin signaling, increases NOTUM expression and stem-like properties of CRC cells, thus suggesting that targeting FASN upstream of the β-catenin/NOTUM axis may be an effective preventative therapeutic strategy for CRC.
Document Type
Article
Publication Date
10-2024
Digital Object Identifier (DOI)
https://doi.org/10.3390/cells13191663
Funding Information
This research was funded by NCI R01 CA249734 (Y.Y.Z.), NCI R01 CA208343 (B.M.E.), NCI R01 CA284532 (B.M.E.), and NCI T32 CA165990 (C.O.K.).
Repository Citation
Kelson, Courtney O.; Tessmann, Josiane Weber; Geisen, Mariah E.; He, Daheng; Wang, Chi; Gao, Tianyan; Evers, B. Mark; and Zaytseva, Yekaterina Y., "Upregulation of Fatty Acid Synthase Increases Activity of β-Catenin and Expression of NOTUM to Enhance Stem-like Properties of Colorectal Cancer Cells" (2024). Markey Cancer Center Faculty Publications. 235.
https://uknowledge.uky.edu/markey_facpub/235
Notes/Citation Information
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).