TY  - JOUR
AU  - Kong, Yue
AU  - Liu, Yugeng
AU  - Li, Xianzhe
AU  - Rao, Menglan
AU  - Li, Dawei
AU  - Ruan, Xiaolan
AU  - Li, Shanglin
AU  - Jiang, Zhenyou
AU  - Zhang, Qiang
TI  - Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis.
JO  - Journal of translational medicine
VL  - 21
IS  - 1
SN  - 1479-5876
CY  - London
PB  - BioMed Central
M1  - DKFZ-2023-02373
SP  - 826
PY  - 2023
N1  - #EA:C070#
AB  - Protein palmitoylation, which is catalyzed by palmitoyl-transferase and de-palmitoyl-transferase, plays a crucial role in various biological processes. However, the landscape and dynamics of protein palmitoylation in human cancers are not well understood.We utilized 23 palmitoyl-acyltransferases and seven de-palmitoyl-acyltransferases as palmitoylation-related genes for protein palmitoylation analysis. Multiple publicly available datasets were employed to conduct pan-cancer analysis, examining the transcriptome, genomic alterations, clinical outcomes, and correlation with c-Myc (Myc) for palmitoylation-related genes. Real-time quantitative PCR and immunoblotting were performed to assess the expression of palmitoylation-related genes and global protein palmitoylation levels in cancer cells treated with Myc depletion or small molecule inhibitors. Protein docking and drug sensitivity analyses were employed to predict small molecules that target palmitoylation-related genes.We identified associations between palmitoylation and cancer subtype, stage, and patient survival. We discovered that abnormal DNA methylation and oncogenic Myc-driven transcriptional regulation synergistically contribute to the dysregulation of palmitoylation-related genes. This dysregulation of palmitoylation was closely correlated with immune infiltration in the tumor microenvironment and the response to immunotherapy. Importantly, dysregulated palmitoylation was found to modulate canonical cancer-related pathways, thus influencing tumorigenesis. To support our findings, we performed a proof-of-concept experiment showing that depletion of Myc led to reduced expression of most palmitoylation-related genes, resulting in decreased global protein palmitoylation levels. Through mass spectrometry and enrichment analyses, we also identified palmitoyl-acyltransferases ZDHHC7 and ZDHHC23 as significant contributors to mTOR signaling, DNA repair, and immune pathways, highlighting their potential roles in tumorigenesis. Additionally, our study explored the potential of three small molecular (BI-2531, etoposide, and piperlongumine) to modulate palmitoylation by targeting the expression or activity of palmitoylation-related genes or enzymes.Overall, our findings underscore the critical role of dysregulated palmitoylation in tumorigenesis and the response to immunotherapy, mediated through classical cancer-related pathways and immune cell infiltration. Additionally, we propose that the aforementioned three small molecule hold promise as potential therapeutics for modulating palmitoylation, thereby offering novel avenues for cancer therapy.
KW  - Cancer (Other)
KW  - DNA methylation (Other)
KW  - Immunotherapy (Other)
KW  - Palmitoylation (Other)
KW  - Small molecular (Other)
KW  - c-Myc (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37978524
C2  - pmc:PMC10655258
DO  - DOI:10.1186/s12967-023-04611-8
UR  - https://inrepo02.dkfz.de/record/285439
ER  -