RESUMEN
SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is an important epigenetic regulator catalyzing histone H3 lysine 9 (H3K9) methylation, specifically di-/tri-methylation. This regulation promotes gene silencing through heterochromatin formation. Aberrant SETDB1 expression, and its oncogenic role is evident in many cancers. Thus, SETDB1 is a valid target with novel therapeutic benefits. In this review, we explore the structural and biochemical features of SETDB1, its regulatory mechanisms, and its role in various cancers. We also discuss recent discoveries in small molecules targeting SETDB1 and provide suggestions for future research.
Asunto(s)
Epigénesis Genética , N-Metiltransferasa de Histona-Lisina , Neoplasias , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Histonas/metabolismo , Terapia Molecular DirigidaRESUMEN
INTRODUCTION: Polo like kinase (PLK) is known to play a pivotal role in various cell cycle processes to perpetuate proper division and growth of the cells. Polo like kinase-4 (PLK4) is one such kinase that appears in low abundance and plays a well-characterized role in centriole duplication. PLK4 deregulation (i.e. both overexpression and depletion of PLK4), leads to altered mitotic fidelity and thereby triggers tumorigenesis. Hence, over the last few years PLK4 has emerged as a potential therapeutic target for the treatment of various advanced cancers. Areas covered: In this review, we discuss the basic structure, expression, localization and functions of PLK4 along with its regulation by various proteins. We also discuss the role of altered PLK4 activity in the onset of cancer and the current pre-clinical and clinical inhibitors to regulate PLK4. Expert opinion: PLK4 mediated centriole duplication has a crucial role in maintaining mitotic correctness in normal cells, while its deregulation has a greater impact on genesis of cancer. Henceforth, a deep knowledge of the PLK4 levels, its role and interactions with various proteins in cancer is required to design effective inhibitors for clinical use.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Centriolos/metabolismo , Diseño de Fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Mitosis/fisiología , Neoplasias/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
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.
