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Maspin increases Ku70 acetylation and Bax-mediated cell death in cancer cells
Sook-Ja Lee1, Haerim Jang, Chaehwa Park
1Cancer Genetics Laboratory, Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
Abstract:
Ku70, a DNA repair protein, was recently identified as a critical anti-apoptotic protein that inhibits Bax translocation to mitochondria. The dissociation of Bax from Ku70 is essential for the apoptotic activity of Bax. Here, we show that maspin, a tumor suppressor protein frequently lost in cancer, regulates this process. Maspin increased cell death in a Ku70 acetylation-dependent manner. Maspin inhibited histone deacetylase 1 (HDAC1) and thus increased the acetylation of Ku70 and the dissociation of Bax from Ku70, which led to the induction of apoptosis. These results reveal maspin as a Ku70-interacting molecule and provide the basis for a new endogenous acetylation-based control mechanism that reduces Ku70-mediated sequestration of Bax from mitochondria.
Insights
Maspin, a tumor suppressor, triggers cell death by increasing Ku70 acetylation. This acetylation releases Bax, initiating apoptosis and revealing a new acetylation-based control mechanism in cancer research.
Area of Science:
- Cellular biology
- Molecular oncology
- Biochemistry
Background:
- Ku70 (X-ray repair cross-complementing protein 1) is a DNA repair protein with anti-apoptotic functions.
- Ku70 sequesters Bax, preventing its translocation to mitochondria and inhibiting apoptosis.
- Maspin, a tumor suppressor, is often lost in various cancers, suggesting a role in cancer progression.
Purpose of the Study:
- To investigate the role of maspin in regulating Ku70-mediated inhibition of apoptosis.
- To elucidate the molecular mechanism by which maspin influences Bax-Ku70 interaction.
- To identify maspin as a potential therapeutic target in cancer treatment.
Main Methods:
- Cell-based assays to measure apoptosis and cell death.
- Immunoprecipitation to study protein-protein interactions (Bax-Ku70).
- Western blotting to assess protein acetylation and expression levels.
- Enzyme activity assays for histone deacetylase 1 (HDAC1).
Main Results:
- Maspin treatment led to increased cell death, dependent on Ku70 acetylation.
- Maspin inhibited the activity of histone deacetylase 1 (HDAC1).
- Maspin treatment resulted in increased acetylation of Ku70, promoting Bax dissociation from Ku70.
- This dissociation facilitated Bax translocation to mitochondria, inducing apoptosis.
Conclusions:
- Maspin acts as a regulator of apoptosis by modulating Ku70 acetylation.
- Maspin inhibits HDAC1, leading to enhanced Ku70 acetylation and subsequent Bax release.
- These findings reveal maspin as a novel Ku70-interacting protein and an endogenous acetylation-based mechanism controlling Bax-mediated apoptosis.
