Protein palmitoylation and cancer

Ko, Pin‐Joe; Dixon, Scott J.

doi:10.15252/embr.201846666

Cited by 259 publications

(242 citation statements)

References 144 publications

(233 reference statements)

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“…Palmitoyl‐CoA as an immediate metabolite of dietary PA could also directly be involved in the palmitoylation of an array of proteins, and promote these proteins’ mediated tumor progression . For example, dietary PA could elevate levels of palmitoylated proteins, such as Sonic Hedgehog protein (Shh).…”

Section: Discussionmentioning

confidence: 99%

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

et al. 2019

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Numerous genetic alterations have been identified during prostate cancer progression. The influence of environmental factors, particularly the diet, on the acceleration of tumor progression is largely unknown. Expression levels and/or activity of Src kinase are highly elevated in numerous cancers including advanced stages of prostate cancer. In this study, we demonstrate that high-fat diets (HFDs) promoted pathological transformation mediated by the synergy of Src and androgen receptor in vivo. Additionally, a diet high in saturated fat significantly enhanced proliferation of Src-mediated xenograft tumors in comparison with a diet high in unsaturated fat. The saturated fatty acid palmitate, a major constituent in a HFD, significantly upregulated the biosynthesis of palmitoyl-CoA in cancer cells in vitro and in xenograft tumors in vivo. The exogenous palmitate enhanced Src-dependent mitochondrial β-oxidation. Additionally, it elevated the amount of C16-ceramide and total saturated ceramides, increased the level of Src kinase localized in the cell membrane, and Src-mediated downstream signaling, such as the activation of mitogen-activated protein kinase and focal adhesion kinase. Our results uncover how the metabolism of dietary palmitate cooperates with elevated Src kinase in the acceleration of prostate tumor progression. K E Y W O R D S palmitate/fatty acid metabolism/Src kinase/prostate cancer 1 | INTRODUCTION Prostate cancer is the most common cancer in men and one of the leading causes of cancer-related deaths in developed countries. 1 Diet is considered a critical environmental risk factor in prostate cancer progression. 2 Numerous epidemiological studies indicate that obesity, higher body mass index, or adult weight gain significantly increases the risk of aggressive prostate cancer, mortality, and recurrence of prostate cancer. 3-8 A high-fat diet (HFD) or certain dietary saturated fatty acids (FAs) including palmitic acid (PA) and myristic acid (MA) are associated with advanced stages of prostate cancer and increase the risk of prostate cancer-specific mortality. 3,5,7,9 Incorporation of excess free FAs into cancer cell membranes promotes cancer invasion by reduction of cell-cell contact and increase of surface adhesion. 10 However, the interaction of dietary factors with oncogenic events to regulate tumor progression is not well-understood. Numerous genetic alterations including aberrant expression and/ or loss of tumor suppressor genes have been identified in the initiation and progression of prostate tumors. 11 Among those oncogenic events, overexpression and/or activation of Src kinase is common in advanced stages of prostate cancer. 12,13 Src kinase is a pleiotropic activator to mediate numerous signal transduction pathways initiated by G-protein coupled receptors, β1-integrin, growth factor receptors, and others. 14,15 The activation of Src kinase promotes cell survival, proliferation, migration, and invasion in The Prostate. 2019;79:896-908. wileyonlinelibrary.com/journal/pros

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Section: Discussionmentioning

confidence: 99%

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

et al. 2019

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“…Additionally, palmitoylation tethers proteins into membrane microdomains such as lipid rafts, thus modulating protein activity, stability, and multiprotein complex formation 4 . Palmitoylation is frequently altered in various diseases including cancer 3,5 . However, the biological role of this PTM is complex and multifaceted and has not been fully investigated due to technical challenges associated with the low abundance of palmitoyl-proteins in general, the difficulty of enriching palmitoyl-proteins with high specificity, and the high hydrophobicity of intact palmitoyl-peptides.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive palmitoyl-proteomic analysis identifies distinct protein signatures for large and small cancer-derived extracellular vesicles

Mariscal

Vagner

Kim

et al. 2019

Preprint

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Extracellular vesicles (EVs) are membrane-enclosed particles that play an important role in cancer progression and have emerged as a promising source of circulating biomarkers. Protein S-acylation, also known as palmitoylation, has been proposed as a post-translational mechanism that modulates the dynamics of EV biogenesis and protein cargo sorting. However, technical challenges have limited large-scale profiling of the whole palmitoyl-proteins of EVs. We successfully employed a novel approach that combines low-background acyl-biotinyl exchange (LB-ABE) with label-free proteomics to analyze the palmitoyl proteome of large EVs (L-EVs) and small EVs (S-EVs) from prostate cancer cells. Here we report the first palmitoyl-protein signature of EVs, and demonstrate that L-and S-EVs harbor proteins associated with distinct biological processes and subcellular origin. We identified STEAP1, STEAP2, and ABBC4 as prostate cancer-specific palmitoyl proteins enriched in both EV populations in comparison with the originating cell lines. Importantly, the presence of the above proteins in EVs was significantly reduced upon inhibition of palmitoylation in the producing cells. These results suggest that palmitoylation may be involved in the differential sorting of proteins to distinct EV populations and allow for better detection of disease biomarkers.

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“…minutes and centrifuging the cell lysate at 13,000-18,000 × g at 4°C for 5 minutes, we transferred the supernatant to a clean tube and determine the protein concentration using 11 the EZQ® Protein Quantitation Kit (Cat. no.…”

Section: Click-it Identification Of Pd-l1 Palmitoylationmentioning

confidence: 99%

Palmitoylation is critically required for cancer intrinsic PD-1 expression and functions

Brosseau

et al. 2019

Preprint

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Programmed cell death protein 1 (PD-1) is a crucial anticancer target, but the relatively low response rate and acquired resistance to existing antibody drugs highlight an urgent need to develop alternative targeting strategies. Here we report the palmitoylation of PD-1, discovered the main DHHC enzyme for this modification, revealed the mechanism for its effect on PD-1 expression, and rationally developed a peptide for targeting PD-1 expression. Palmitoylation promoted the trafficking of PD-1 to recycling endosome, thus preventing its lysosome-dependent degradation. Palmitoylation was required for the activation of PD-1 downstream signaling, and targeting palmitoylation by pharmacological inhibitor or depleting the modification enzyme caused significant anti-tumor effects. A peptide was designed to competitively inhibit PD-1 palmitoylation and expression, opening a new route for developing PD-1 inhibitors as a strategy for cancer immunotherapy. SignificanceWe show for the first time that PD-1 is palmitoylated, identify DHHC9 as the predominant enzyme for its palmitoylation, and reveal the molecular mechanisms underlying its effects on PD-1 stability and functions. Importantly, we also designed a competitive inhibitor targeting PD-1 palmitoylation, and this first-in-class molecule may inspire the development of new checkpoint inhibitors.

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Protein palmitoylation and cancer

Cited by 259 publications

References 144 publications

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

Comprehensive palmitoyl-proteomic analysis identifies distinct protein signatures for large and small cancer-derived extracellular vesicles

Palmitoylation is critically required for cancer intrinsic PD-1 expression and functions

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