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Updated: Oct 11, 2025
Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
Published on: February 27, 2016
The deacetylation of Foxk2 by Sirt1 reduces chemosensitivity to cisplatin
Xi-Wen Wang1,2,3, Qi-Qiang Guo1,2, Yang Yu1,2
1College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China.
Abstract:
In multiple types of cancer, decreased tumour cell apoptosis during chemotherapy is indicative of decreased chemosensitivity. Forkhead box K2 (FOXK2), which is essential for cell fate, regulates cancer cell apoptosis through several post-translational modifications. However, FOXK2 acetylation has not been extensively studied. Here, we evaluated the effects of sirtiun 1 (SIRT1) on FOXK2 deacetylation. Our findings demonstrated that SIRT1 inhibition increased FOXK2-induced chemosensitivity to cisplatin and that K223 in FOXK2 was acetylated. Furthermore, FOXK2 K223 deacetylation reduced chemosensitivity to cisplatin in vitro and in vivo. Mechanistically, FOXK2 was acetylated by the acetyltransferase cAMP response element binding protein and deacetylated by SIRT1. Furthermore, cisplatin attenuated the interaction between FOXK2 and SIRT1. Cisplatin or SIRT1 inhibition enhanced FOXK2 acetylation, thereby reducing the nuclear distribution of FOXK2. Additionally, FOXK2 K223 acetylation significantly affected the expression of cell cycle-related and apoptosis-related genes in cisplatin-stimulated cancer cells, and FOXK2 K223 hyperacetylation promoted mitotic catastrophe, which enhanced chemosensitivity to cisplatin. Overall, our results provided insights into the mechanisms of SIRT1-mediated FOXK2 deacetylation, which was involved in chemosensitivity to cisplatin.
Insights
SIRT1 deacetylation of FOXK2 (Forkhead box K2) reduces cisplatin sensitivity in cancer. Inhibiting SIRT1 or acetylating FOXK2 K223 enhances chemosensitivity by promoting mitotic catastrophe.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- Decreased tumor cell apoptosis during chemotherapy correlates with reduced chemosensitivity.
- Forkhead box K2 (FOXK2) regulates cancer cell apoptosis, but its acetylation is not well understood.
- Sirtuin 1 (SIRT1) is a deacetylase with potential roles in cancer progression.
Purpose of the Study:
- To investigate the role of SIRT1 in FOXK2 deacetylation.
- To determine the impact of FOXK2 acetylation and deacetylation on chemosensitivity to cisplatin.
- To elucidate the underlying molecular mechanisms linking SIRT1, FOXK2, and cisplatin response.
Main Methods:
- Assessing the effect of SIRT1 inhibition on FOXK2-induced chemosensitivity.
- Identifying and analyzing the acetylation site K223 in FOXK2.
- Investigating the interaction between FOXK2, SIRT1, and cisplatin using in vitro and in vivo models.
- Examining gene expression related to cell cycle and apoptosis.
Main Results:
- SIRT1 inhibition increased chemosensitivity to cisplatin, linked to FOXK2 acetylation at K223.
- FOXK2 K223 deacetylation reduced chemosensitivity.
- Cisplatin treatment attenuated the interaction between FOXK2 and SIRT1, enhancing FOXK2 acetylation.
- FOXK2 K223 acetylation promoted mitotic catastrophe and enhanced cisplatin chemosensitivity.
Conclusions:
- SIRT1 mediates FOXK2 deacetylation, influencing chemosensitivity to cisplatin.
- FOXK2 acetylation, particularly at K223, enhances chemosensitivity by promoting mitotic catastrophe.
- Targeting the SIRT1-FOXK2 pathway offers a potential strategy to improve cisplatin-based cancer therapy.
