Emerging role of SETDB1 as a therapeutic target

ABSTRACT

Introduction: Epigenetic changes lead to aberrant gene expression in cancer. SETDB1, a histone lysine methyltransferase plays an important role in methylation and gene silencing. Aberrant histone methylation at H3K9 by SETDB1 promotes silencing of tumor suppressor genes and thus contributes to carcinogenesis. Recent studies indicate that SETDB1 is abnormally expressed in various human cancer conditions which contributed to enhanced tumor growth and metastasis. Hence, SETDB1 appears to be a promising epigenetic target for therapeutic intervention.

Areas covered: In this article, the structural features, localization and functions of SETDB1 are reviewed. Also, an overview of the role of SETDB1 in cancer and other disease mechanisms, the currently studied inhibitors for SETDB1 are mentioned.

Expert opinion: Silencing of tumor suppressor genes due to excessive trimethylation at H3K9 by amplified SETDB1 levels is found in various cancerous conditions. Since epigenetic changes are reversible, SETDB1 holds promise as an important therapeutic target for cancer. Therefore, a better understanding of the role of SETDB1 and its interaction with various proteins in cancer-related mechanisms along with therapeutic interventions specific for SETDB1 may improve targeted cancer therapy.

KEYWORDS:

• Cancer
• DZNep
• gene silencing
• H3K9 trimethylation
• mithramycin
• SETDB1

Article highlights

• SETDB1, a histone methyltransferase (HMT) is involved in methylation of histone H3 on lysine 9 position (H3K9).

• SETDB1 also plays role in gene silencing, PML-NB associated functions, early embryo development and in embryonic stem cells.

• Epigenetic deregulation of SETDB1 expression results in various cancers such as melanoma, lung cancer, ovarian cancer, hepatocellular carcinoma and breast cancer.

• Mithramycin A and 3-Deazaneplanocin A exhibited anticancer activity via suppressing SETDB1 mediated trimethylation and inducing apoptosis in cancerous cells.

• Based on the currently available information, SETDB1 holds considerable value as a potential target for cancer.

• Development of SETDB1-selective inhibitors may be a valuable therapeutic strategy for improved cancer treatment.

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Declaration of interest

The authors are employees of Jubilant Biosys Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.