Acetylation of JUP at Lys326 promotes gastric cancer progression by enhancing TCF4 transcriptional activity
- 1Xinxiang Central Hospital
- 2Henan Medical University
Abstract
Background: Non-histone acetylation is increasingly implicated in cancer, but the molecular switch governing the context-dependent oncogenic activity of junction plakoglobin (JUP) in gastric cancer (GC) remains unknown.
Methods: Quantitative lysine acetylproteomics and transcriptomic profiling were integrated in 10 paired primary GC and adjacent nontumor tissues. Site-directed JUP mutants, biochemical and molecular assays, functional studies in HGC-27 and MKN-45 cells, xenograft experiments, and analysis of 100 clinical specimens were used to define the regulation, mechanism, and clinical relevance of JUP acetylation.
Results: Acetylproteomics identified 1,054 hyperacetylated proteins, with JUP emerging as a central network hub. JUP acetylation was increased in GC despite unchanged total JUP protein and mRNA levels. Lys326 (K326) was identified as the predominant functional acetylation site. The acetylation-mimetic K326Q mutant prolonged JUP half-life and enhanced colony formation, migration, invasion, and xenograft growth, whereas K326R produced opposing effects. EP300 and SIRT7 were identified as the acetyltransferase and deacetylase, respectively, controlling JUP K326 acetylation. Mechanistically, K326 acetylation promoted nuclear colocalization and association of JUP with TCF4, increased MYC, CCND1, and MMP7 expression, and drove malignant phenotypes that were abolished by TCF4 silencing. In clinical specimens, high JUP K326 acetylation was associated with advanced tumor stage and poorer survival.
Conclusion: This study identifies a previously unrecognized EP300/SIRT7-JUP(K326ac)-TCF4 axis that converts JUP from a junctional protein into an oncogenic transcriptional co-regulator. JUP K326 acetylation may serve as a modification-specific biomarker and a tractable therapeutic vulnerability in GC.
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BibTeX
@article{zhang2026acetylation,
title = {{Acetylation of JUP at Lys326 promotes gastric cancer progression by enhancing TCF4 transcriptional activity}},
author = {Fucheng Zhang and Jiaxing Liu and Qiurong Li and Danyang Chang and Lipei Zhao and Yuhou Shen and Haifang Zhao and Xinyue Huang and Ruxia Sheng and Aimin Yue},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1949454},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1949454/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Acetylation of JUP at Lys326 promotes gastric cancer progression by enhancing TCF4 transcriptional activity
AU - Fucheng Zhang
AU - Jiaxing Liu
AU - Qiurong Li
AU - Danyang Chang
AU - Lipei Zhao
AU - Yuhou Shen
AU - Haifang Zhao
AU - Xinyue Huang
AU - Ruxia Sheng
AU - Aimin Yue
PY - 2026
DA - 2026/10/20
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1949454
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1949454/full
AB - Background: Non-histone acetylation is increasingly implicated in cancer, but the molecular switch governing the context-dependent oncogenic activity of junction plakoglobin (JUP) in gastric cancer (GC) remains unknown. Methods: Quantitative lysine acetylproteomics and transcriptomic profiling were integrated in 10 paired primary GC and adjacent nontumor tissues. Site-directed JUP mutants, biochemical and molecular assays, functional studies in HGC-27 and MKN-45 cells, xenograft experiments, and analysis of 100 clinical specimens were used to define the regulation, mechanism, and clinical relevance of JUP acetylation. Results: Acetylproteomics identified 1,054 hyperacetylated proteins, with JUP emerging as a central network hub. JUP acetylation was increased in GC despite unchanged total JUP protein and mRNA levels. Lys326 (K326) was identified as the predominant functional acetylation site. The acetylation-mimetic K326Q mutant prolonged JUP half-life and enhanced colony formation, migration, invasion, and xenograft growth, whereas K326R produced opposing effects. EP300 and SIRT7 were identified as the acetyltransferase and deacetylase, respectively, controlling JUP K326 acetylation. Mechanistically, K326 acetylation promoted nuclear colocalization and association of JUP with TCF4, increased MYC, CCND1, and MMP7 expression, and drove malignant phenotypes that were abolished by TCF4 silencing. In clinical specimens, high JUP K326 acetylation was associated with advanced tumor stage and poorer survival. Conclusion: This study identifies a previously unrecognized EP300/SIRT7-JUP(K326ac)-TCF4 axis that converts JUP from a junctional protein into an oncogenic transcriptional co-regulator. JUP K326 acetylation may serve as a modification-specific biomarker and a tractable therapeutic vulnerability in GC.
SN - 2234-943X
ER -