# Palmitic acid activates c-Myc via dual palmitoylation-dependent pathways to promote colon cancer

## TL;DR

This study shows that palmitic acid activates the c-Myc protein through two palmitoylation pathways, promoting colon cancer growth and offering new treatment targets.

## Contribution

The discovery of palmitic acid's role in activating c-Myc via dual palmitoylation pathways in colon cancer is novel.

## Key findings

- Palmitic acid activates c-Myc through palmitoylation by ZDHHC9, enhancing its transcriptional activity.
- c-Myc transactivates FATP2 to increase PA uptake, forming a feedforward loop in tumor progression.
- Inhibiting ZDHHC9 and FATP2 suppresses c-Myc function and tumor burden in xenograft models.

## Abstract

c-Myc is broadly hyperactivated in colon cancer, yet the mechanisms sustaining its transcriptional activation remain elusive. Here we identify palmitic acid (PA) as a metabolite cue that activates c-Myc via dual palmitoylation-dependent pathways operating across tumor initiation and progression. In colitis models, PA-rich diets exacerbate inflammation and enrich MYC target programs without increasing Myc mRNA. Mechanistically, the palmitoyltransferase ZDHHC9, upregulated by IL-1β, directly palmitoylates c-Myc at C171, enhancing c-Myc/MAX dimerization and transcriptional activity; genetic or pharmacologic inhibition diminishes c-Myc palmitoylation and target gene expression. During tumor progression, c-Myc transactivates FATP2, increasing PA uptake and reinforcing c-Myc palmitoylation, thereby establishing a feedforward loop and metabolic addiction to PA. Functionally, PA accelerates xenograft growth, whereas targeting ZDHHC9 and FATP2 inhibits c-Myc function to suppress tumor burden. These findings uncover metabolite-driven control of c-Myc through palmitoylation and highlight ZDHHC9/FATP2 as actionable vulnerabilities for colon cancer treatment.