EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression

Abstract

Gliomas with mutant p53 occurring in 30% of glioma patients exhibit therapeutic resistance and poor outcomes. In this study, we identify a novel mechanism through which mutant p53 drives cancer cell survival and malignant growth. We documented overexpression of the zinc finger protein ZDHHC5 in glioma compared with normal brain tissue and that this event tightly correlated with p53 mutations. Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2. Taken together, our work highlighted ZDHHC5 as a candidate therapeutic target for management of p53-mutated gliomas.

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

“…Furthers studies to understand how these proteins are incorporated into EVs may yield important insights into cancer progression. Interestingly, S-EVs contain the palmitoylated form of the palmitoyl-transferase ZDHHC5, which palmitoylates EZH2, one of the major transcription factors in prostate cancer progression 55 . This suggests that prostate cancer S-EVs may promote the transformation of other cells by inducing horizontal EV transfer of EZH2; however, further investigation is required.…”

Protein palmitoylation and cancer

“…In lung cancer, ZDHHC5 expression levels are not associated with overall survival, but short interfering RNA (siRNA)-mediated silencing of ZDHHC5 leads to reduced cell proliferation, colony formation, cell migration, and xenograft tumor growth [86]. By contrast, in glioma cells, high ZDHHC5 expression is predictive of poorer prognosis, and this overexpression appears to be driven by oncogenic mutations in the tumor suppressor protein p53 [87]. These results suggest that individual ZDHHC enzymes can act as either oncoproteins or tumor suppressors in a tissue-specific and/or cancer type-specific manner.…”

“…Cancer links is defined broadly as any literature link between a ZDHHC-family member and a particular cancer, including large-scale and small-scale experimental studies, animal and cell culture studies, and clinical studies, whether functional or correlative. References: ZDHHC2[70,129,130], ZDHHC3[131][132][133], ZDHHC5[87], ZDHHC7[47,134], ZDHHC9[89,92,135,136], ZDHHC11[77,78,137,138], ZDHHC13[49,73], ZDHHC14[82][83][84][85], ZDHHC20[81], ZDHHC23[139]. HPA, Human Protein Atlas (www.proteinatlas.org/).…”

Palmitoylation stabilizes PD-L1 to promote breast tumor growth

“…1a, b, PD-L1 protein level significantly decreased upon 2-BP treatment in a dose-and time-dependent manner, suggesting that PD-L1 expression is regulated by protein palmitoylation. On the basis of prior studies, 9,11 which indicated that palmitoylation could regulate protein stability, we speculated that PD-L1 itself undergoes palmitoylation to maintain stability. To validate this hypothesis, we subjected PD-L1 Flag -expressing MDA-MB-231 (MB231-PD-L1 Flag ) and BT549 (BT549-PD-L1 Flag ) breast cancer cells to acyl-biotin exchange (ABE) assays in which free cysteine thiol groups of the proteins are irreversibly blocked by N-ethylmaleimide (NEM), whereas palmitoylated cysteines are later cleaved by hydroxylamine (HAM) and biotinylated.…”

“…palmitoyltransferase of EZH2, significantly inhibits glioma tumor growth. 9 Thus, palmitoylation or palmitoyltransferases could be novel targets for cancer therapy. In the current study, we searched for other possible metabolic-related modifications of PD-L1 such as lipid modification, and unexpectedly discovered that palmitoylation occurred on PD-L1 and played an important role in PD-L1 stability.…”