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Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer
Miku Wada1, Asako Kukita1, Kenbun Sone1
1Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Abstract:
The histone methyltransferase SETD8, which methylates the lysine 20 of histone H4 (H4K20), is reportedly involved in human carcinogenesis along with nonhistone proteins such as p53. However, its expression profiles and functions in the context of high-grade serous ovarian carcinoma (HGSOC) are still unknown. The purpose of this study was to investigate the role of SETD8 in HGSOC. We performed quantitative real-time PCR and immunohistochemistry to detect the expression of SETD8 in HGSOC samples and normal ovarian specimens. Then, we assessed the effect of the inhibition of SETD8 expression using small interfering RNA (siRNA) and a selective inhibitor (UNC0379) on cell proliferation and apoptosis in HGSOC cells. The expression of SETD8 was significantly upregulated in clinical ovarian cancer specimens compared to that in the corresponding normal ovary. In addition, suppression of SETD8 expression in HGSOC cells with either siRNA or UNC0379 resulted in reduced levels of H4K20 monomethylation, inhibition of cell proliferation, and induction of apoptosis. Furthermore, UNC0379 showed a long-term antitumor effect against HGSOC cells, as demonstrated by colony-formation assays. SETD8 thus constitutes a promising therapeutic target for HGSOC, warranting further functional studies.
Insights
The histone methyltransferase SETD8 is upregulated in high-grade serous ovarian carcinoma (HGSOC). Inhibiting SETD8 reduces cancer cell proliferation and promotes apoptosis, suggesting it as a therapeutic target for HGSOC.
Area of Science:
- Epigenetics
- Molecular Biology
- Oncology
Background:
- SETD8 (histone methyltransferase) methylates histone H4 at lysine 20 (H4K20).
- SETD8 is implicated in human carcinogenesis.
- SETD8's role in high-grade serous ovarian carcinoma (HGSOC) is uncharacterized.
Purpose of the Study:
- To investigate SETD8 expression and function in HGSOC.
- To determine if SETD8 is a potential therapeutic target for HGSOC.
Main Methods:
- Quantitative real-time PCR and immunohistochemistry for SETD8 expression analysis.
- Small interfering RNA (siRNA) and a selective inhibitor (UNC0379) to suppress SETD8.
- Assessment of cell proliferation and apoptosis in HGSOC cells.
- Colony-formation assays to evaluate long-term antitumor effects.
Main Results:
- SETD8 expression is significantly upregulated in HGSOC tissues compared to normal ovarian tissues.
- SETD8 suppression (via siRNA or UNC0379) reduced H4K20 monomethylation levels.
- Inhibition of SETD8 led to decreased HGSOC cell proliferation and induced apoptosis.
- UNC0379 demonstrated a sustained antitumor effect on HGSOC cells.
Conclusions:
- SETD8 is upregulated in HGSOC and contributes to cancer cell proliferation.
- SETD8 inhibition effectively reduces HGSOC cell growth and induces apoptosis.
- SETD8 represents a promising therapeutic target for HGSOC treatment.
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