SUZ12 promotes pancreatic ductal adenocarcinoma progression and chemoresistance by epigenetically silencing NCOA4-induced ferroptosis
Year: 2025
Type: article
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive nature and high propensity to metastasize, resulting in a low overall survival rate. Identifying effective molecular targets for treatment and enhancing sensitivity to gemcitabine (GEM) could significantly improve the management of PDAC patients. SUZ12 has been implicated in the progression of several malignancies, but its associations with PDAC, ferroptosis and GEM sensitivity remain unclear. To investigate the relationship between SUZ12 and PDAC, bioinformatic analyses are performed, and the results reveal that higher levels of SUZ12 expression in patients with PDAC are associated with poor prognosis. Studies using in vitro cell lines and in vivo xenograft mouse models have shown that SUZ12 promotes cell proliferation and increases the tumor-forming ability of PDAC cell lines. The mechanistic basis by which SUZ12 regulates PDAC involves its binding to the transcription factor YBX1 and subsequent recruitment of the complex to the NCOA4 promoter region. This recruitment mediates the epigenetic silencing of NCOA4 through the deposition of the repressive histone mark trimethylation of histone H3 at lysine 27 (H3K27me3) at the promoter. Consequently, this silencing enhances the cellular antioxidant capacity and suppresses ferroptosis in PDAC. SUZ12 expression is found to be elevated in GEM-resistant (GR) PDAC cells, and decrease of SUZ12 levels increases GEM sensitivity in PDAC cells. The combination of SUZ12 knockout with GEM shows enhanced synergistic effects in cancer therapy and sensitizes GR cells to GEM, providing new insights into overcoming GEM resistance and highlighting SUZ12 as a potential target for clinical intervention in PDAC patients.
DOI: 10.3724/abbs.2025215
Authors: Lei Yin, Borui Li, Yunhai Wei, Zheng Li, Yang Yang, Jinyu Zhang, Guixiong Fan, Desheng Jing, Yadong Shi, Haochun Yuan, Xiaowu Xu, Xuemin Chen
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4416124860