KEY TAKEAWAYS
- The study aimed to investigate the role of SIRT1-mediated deacetylation of FOXO3 in regulating mitophagy and hormone resistance in endometrial cancer.
- Researchers found that SIRT1-mediated FOXO3 deacetylation is key to mitophagy and hormone resistance in EC.
Endometrial cancer (EC) is a common gynecological malignancy, particularly prevalent in developed countries, with its incidence rising due to lifestyle changes and an aging population. Treatment for EC varies and includes surgery, radiation therapy, chemotherapy, and hormone therapy. Despite its significance, the complex relationship between Sirtuin 1 (SIRT1) and FOXO3 in EC remains poorly understood.
Xuehua Wei and the team sought to evaluate how SIRT1-mediated deacetylation of FOXO3 influences these factors, uncovering its essential role in regulating both mitophagy and hormone resistance.
They performed an inclusive analysis using high-throughput sequencing, cell experiments, and bioinformatics tools to explore the roles and interactions of SIRT1 and FOXO3 in EC. Co-immunoprecipitation (Co-IP) assays were conducted to evaluate the interaction between SIRT1 and FOXO3 in RL95-2 cells.
Functional assays assessed cell viability, proliferation, migration, invasion, apoptosis, and related gene and protein expression. A mouse model of EC was established to investigate tumor growth and hormone resistance under various interventions. Additionally, immunohistochemistry and TUNEL assays were employed to examine protein expression and apoptosis in tumor tissues. Patients with EC were included in the study to further validate the findings.
About high-throughput transcriptome sequencing, a close association was revealed between SIRT1, FOXO3, and EC development. Co-immunoprecipitation (Co-IP) demonstrated a protein-protein interaction between SIRT1 and FOXO3. Overexpression of SIRT1 enhanced FOXO3 deacetylation and activity, leading to increased BNIP3 transcription and PINK1/Parkin-mediated mitophagy.
This promotion of mitophagy resulted in enhanced cell proliferation, migration, and invasion, and inhibited apoptosis in vitro. Additionally, it contributed to increased tumor growth and hormone resistance in vivo. These results underscore SIRT1 as a key upstream regulator and a potential therapeutic target in EC.
The study concluded that SIRT1 regulates mitophagy and hormone resistance in EC through the deacetylation of FOXO3. This novel molecular mechanism highlights SIRT1 critical role and suggests potential new therapeutic strategies for targeting EC.
The study received no funds.
Source: https://pubmed.ncbi.nlm.nih.gov/39266959/
Wei X, Xiong X, Wang P, et al. (2024). “SIRT1-mediated deacetylation of FOXO3 enhances mitophagy and drives hormone resistance in endometrial cancer.” Mol Med. 2024;30(1):147. Published 2024 Sep 12. doi:10.1186/s10020-024-00915-7
