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Palmitic Acid Activates c-Myc via Dual Palmitoylation-dependent Pathways to Promote Colon Cancer

ABSTRACT: Transcriptional factor c-Myc plays a crucial role in various types of cancer including colon cancer. c-Myc is hyperactivated during the tumorigenesis and malignant progression of colon cancer, but the mechanisms underlying this transcriptional activation remain largely unknown. Considering that colon cancer is constantly exposed to intestinal metabolites, we wonder whether they play a key role in c-Myc transcriptional activation. Here, we reveal that palmitic acid is essential for the transcriptional activation of c-Myc during both inflammation-driven tumorigenesis and tumor progression. Notably, c-Myc is activated by palmitic acid in dual palmitoylation-dependent pathways  “passive activation under palmitic acid exposure” and “proactive activation through palmitic acid uptake”. Finally, exploiting metabolic addiction to palmitic acid as a vulnerability, we propose a promising therapeutic strategy inhibiting palmitoyltransferase ZDHHC9 and fatty acid transporter FATP2 which exerts favorable therapeutic effects against colon cancer. Together, these findings not only uncover a crucial biological role of palmitic acid on c-Myc activation depending on palmitoylation at distinct stages of colon cancer, but also highlights targeting ZDHHC9 and FATP2 as a promising option for colon cancer treatment.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE299569 | GEO | 2026/02/25

REPOSITORIES: GEO

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Palmitic Acid Activates c-Myc via Dual Palmitoylation-dependent Pathways to Promote Colon Cancer

Project description:Palmitic Acid Activates c-Myc via Dual Palmitoylation-dependent Pathways to Promote Colon Cancer

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TLR9-Driven S-Palmitoylation in Dendritic Cells Reveals Immune and Metabolic Protein Targets

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ZDHHC20-Mediated S-Palmitoylation of YTHDF3 Stabilizes MYC mRNA to Promote Pancreatic Cancer Progression

Project description:Post-translational modifications of malignant transformation and tumor maintenance in pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remains largely unexplored. Here, we used the KPC mouse model to examine the effect of palmitoylation on pancreatic cancer progression. ZDHHC20, upregulated by KRAS, is abnormally overexpressed and associated with poor prognosis in patients with pancreatic cancer. Dysregulation of ZDHHC20 promotes pancreatic cancer progression in a palmitoylation-dependent manner. ZDHHC20 inhibits lysosomal localization and degradation of YTHDF3 through S-palmitoylation of Cys474, which can result in abnormal accumulation of the oncogenic product MYC and thereby promote the malignant phenotypes of cancer cells. Further, we designed a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulated MYC expression and inhibited the progression of KRAS mutant pancreatic cancer. Thus, these findings highlight the therapeutic potential of targeting the ZDHHC20-YTHDF3-MYC signaling axis in pancreatic cancer.

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2022-02-28 | PXD005829 | Pride

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These are male and female mus musculus mRNA expression profiles from whole liver tissue of fatp2 knock-out and wildtype mice. .

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Project description:Protein palmitoylation regulates diverse aspects of cellular function and organization and plays a key role in host immune responses to infection. Palmitoylation also modulates the function and localization of virus-encoded proteins. In Serwa et al. (doi:10.1016/j.chembiol.2015.06.024), we employed chemical proteomics tools, bio-orthogonal palmitic acid analogue (heptadec-16-ynoic acid, YnPal), and a multi-functional capture reagent (AzTB) to study palmitoylation events during infection with three strains of herpes simplex virus (HSV-1[17], HSV-1[KOS], HSV-2[186]). We found that a significant fraction of the viral proteome (twelve HSV-encoded proteins) undergoes palmitoylation; we identified a number of virus membrane glycoproteins, structural proteins, and kinases. Furthermore, we identified palmitoylation sites on five HSV-encoded proteins utilising a complementary methodology (Acyl-RAC). This paper also reports selective HSV-induced alterations to palmitoylation and myristoylation of host proteins.

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