Faculty, Staff and Student Publications

Publication Date

7-1-2025

Journal

Cancer Letters

DOI

10.1016/j.canlet.2025.217695

PMID

40189014

PMCID

PMC12165730

PubMedCentral® Posted Date

7-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Gastric adenocarcinoma (GAC) remains a significant global health challenge, with over a million new cases annually. Peritoneal carcinomatosis (PC), detected in ∼20 % of cases at diagnosis and ∼45 % later, is uniformly fatal, with limited treatment options. This study investigated the role of KAP1 in GAC progression, focusing on its interaction with YAP1 and cancer stemness traits. Analysis of over 596 primary GACs and 72 PC samples revealed that high nuclear KAP1 expression correlates with poor prognosis. KAP1 knockdown reduced oncogenic activity and stemness traits in GAC cells. Mechanistically, KAP1 positively regulates YAP1 transcription by binding to its promoter and reducing H3K27ac levels. Mass spectrometry identified an interaction between KAP1 and HNRNPAB, further modulating YAP1 signaling. Expression of the KRAB domain of ZFP568 without its DNA-binding zinc fingers inhibited both KAP1 and YAP1 expression, significantly reducing colony formation and tumor growth in vivo. Additionally, emerging antisense oligonucleotides (ASOs) targeting KAP1 or YAP1 effectively suppressed mouse tumor progression. These findings establish KAP1 as a critical driver of tumor progression in GAC through YAP1 regulation and HNRNPAB interaction, highlighting its potential therapeutic target. This study advances our understanding and offers a preclinical framework to improve outcomes for GAC.

Keywords

Humans, Stomach Neoplasms, YAP-Signaling Proteins, Animals, Tripartite Motif-Containing Protein 28, Adenocarcinoma, Mice, Signal Transduction, Transcription Factors, Adaptor Proteins, Signal Transducing, Cell Line, Tumor, Disease Progression, Hippo Signaling Pathway, Gene Expression Regulation, Neoplastic, Protein Serine-Threonine Kinases, Male, Female, Cell Proliferation, Mice, Nude

Published Open-Access

yes

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