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ω-3PUFAs Inhibit Gallbladder Cancer Through Enhancing STK31 Methylation
Shuang-Xing Li1,2,3, Wei-Yu Zhu1,2,3, Hai-Ying Peng1,2,3
1Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan Province, China.
Abstract:
Gallbladder cancer (GBC) is an aggressive malignancy with limited treatment options. ω-3PUFAs have known anticancer activity, but their role in GBC remains unclear. The anti-GBC effects of ω-3PUFAs (DHA/EPA) were evaluated using in vitro assays and mouse xenograft models. Epigenetic changes were analyzed by RRBS, MSP, and MethyLight PCR. Downstream mechanisms were explored via proteomics, Co-IP, and Western blot. This study demonstrates that ω-3PUFAs suppress GBC progression by inducing promoter hypermethylation of STK31, which is an oncogene found in GBC by our previous study. MethyLight PCR revealed that ω-3PUFAs treatment significantly increased STK31 promoter methylation in GBC-SD cells from 34.1% ± 20.91% to 89.1% ± 13.11%. Moreover, STK31(DNMT1)/GSK3β pathway and COL4A1 (ITGB1) were particularly associated with ω-3PUFAs' inhibitory mechanisms to GBC. In vivo experimental results demonstrated that ω-3PUFAs significantly inhibited the growth of gallbladder cancer xenografts, with tumor growth inhibition rates of 38.6% for GBC-SD and 50.2% for NOZ at day 33, and effectively suppressed tumor cell metastasis in an intraperitoneal mouse model. This study provides first evidence that ω-3PUFAs target STK31 via epigenetic reprogramming, opening new avenues for dietary intervention and targeted therapy of GBC.
Insights
Omega-3 polyunsaturated fatty acids (ω-3PUFAs) show promise in treating gallbladder cancer (GBC). These fatty acids suppress GBC by epigenetically silencing the STK31 oncogene, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Gallbladder cancer (GBC) is an aggressive malignancy with limited therapeutic options.
- The potential of omega-3 polyunsaturated fatty acids (ω-3PUFAs) in GBC treatment is largely unexplored.
- Previous research identified STK31 as a GBC oncogene.
Purpose of the Study:
- To investigate the anti-GBC effects of ω-3PUFAs (DHA/EPA).
- To elucidate the molecular mechanisms underlying ω-3PUFAs' action in GBC.
- To evaluate the therapeutic potential of ω-3PUFAs in preclinical GBC models.
Main Methods:
- In vitro cell assays and mouse xenograft models were employed.
- Epigenetic modifications were assessed using Reduced Representation Bisulfite Sequencing (RRBS), Methyl Specific PCR (MSP), and MethyLight PCR.
- Downstream signaling pathways were analyzed through proteomics, Co-Immunoprecipitation (Co-IP), and Western blotting.
Main Results:
- ω-3PUFAs significantly suppressed GBC cell proliferation and metastasis in vitro and in vivo.
- Treatment with ω-3PUFAs induced hypermethylation of the STK31 oncogene promoter, reducing its expression.
- MethyLight PCR confirmed a significant increase in STK31 promoter methylation from 34.1% to 89.1% in GBC cells.
- The STK31(DNMT1)/GSK3β pathway and COL4A1 (ITGB1) were identified as key mediators of ω-3PUFAs' anti-GBC effects.
- Tumor growth inhibition rates of 38.6% and 50.2% were observed in GBC xenografts.
Conclusions:
- ω-3PUFAs exert significant anti-GBC effects by epigenetically targeting the STK31 oncogene.
- This study provides the first evidence of ω-3PUFAs-mediated epigenetic reprogramming in GBC.
- These findings suggest ω-3PUFAs as a potential dietary intervention or targeted therapy for gallbladder cancer.
