Use of histone methyltransferase inhibitors in cancer treatment: A systematic review
Ludimila Leite MarzochiCaroline Izak CuzziolCarlos FilhoJuliana Amorim dos SantosMárcia Maria Urbanin Castanhole-NunesÉrika Cristina PavarinoEliete Neves Silva GuerraEny Maria Goloni‐Bertollo
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Prostate cancer is (PCa) the second leading cause of cancer death in males in the United State, with 174,650 new cases and 31,620 deaths estimated in 2019. It has been documented that epigenetic deregulation such as histone modification and DNA methylation contributes to PCa initiation and progression. EZH2 (enhancer of zeste homolog 2), the catalytic subunit of the Polycomb Repressive Complex (PRC2) responsible for H3K27me3 and gene repression, has been identified as a promising target in PCa. In addition, overexpression of other epigenetic regulators such as DNA methyltransferases (DNMT) is also observed in PCa. These epigenetic regulators undergo extensive post-translational modifications, in particular, phosphorylation. AKT, CDKs, PLK1, PKA, ATR and DNA-PK are the established kinases responsible for phosphorylation of various epigenetic regulators.
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A comprehensive understanding of the mechanisms involved in epigenetic changes in gene expression is essential to the clinical management of diseases linked to the SMYD family of lysine methyltransferases. The five known SMYD enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine (SAM) to specific lysines on histones and non-histone substrates. SMYDs family members have distinct tissue distributions and tissue-specific functions, including regulation of development, cell differentiation, and embryogenesis. Diseases associated with SMYDs include the repressed transcription of SMYD1 genes needed for the formation of ion channels in the heart leading to heart failure, SMYD2 overexpression in esophageal squamous cell carcinoma (ESCC) or p53-related cancers, and poor prognosis associated with SMYD3 overexpression in more than 14 types of cancer including breast cancer, colon cancer, prostate cancer, lung cancer, and pancreatic cancer. Given the importance of epigenetics in various pathologies, the development of epigenetic inhibitors has attracted considerable attention from the pharmaceutical industry. The pharmacologic development of the inhibitors involves the identification of molecules regulating both functional SMYD SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domains, a process facilitated by available X-ray structures for SMYD1, SMYD2, and SMYD3. Important leads for potential pharmaceutical agents have been reported for SMYD2 and SMYD3 enzymes, and six epigenetic inhibitors have been developed for drugs used to treat myelodysplastic syndrome (Vidaza, Dacogen), cutaneous T-cell lymphoma (Zoinza, Isrodax), and peripheral T-cell lymphoma (Beleodag, Epidaza). The recently demonstrated reversal of SMYD histone methylation suggests that reversing the epigenetic effects of SMYDs in cancerous tissues may be a desirable target for pharmacological development.
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Abstract Understanding the roles of epigenetic alterations in cancer development and maintenance holds great promise for cancer prevention, detection, and therapy. Cancer can be considered as a pathogenic state where cellular differentiation is suppressed (i.e. stem cell-like) and aberrant epigenetic patterning is commonly observed in tumors. Histone methyltransferases play a key role in epigenetics by modifying key lysine and arginine residues on histones and thereby influencing biological processes. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through over-expression in a variety of cancer types. These reports have shown that pharmacologic inhibition or genetic ablation of G9a leads to retardation of tumor cell growth and cellular invasion in vitro as well as inhibition of metastasis in vivo. To further elucidate the enzymatic role of G9a in cancer, we describe herein the discovery of a novel histone methyltransferase inhibitor, A-366, that selectively inhibits G9a and the closely related GLP (EHMT1). A-366 is a peptide competitive inhibitor of G9a/GLP with in vitro enzymatic IC50 of ∼ 3 nM and cellular activity of ∼ 100 nM and > 100-fold selectivity over other methyltransferases and other non-epigenetic targets. A-366 has significantly less cytotoxic effects on the growth of solid tumor cell lines compared to other known G9a/GLP small molecule inhibitors despite roughly equivalent cellular activity on methylation of H3K9me2. However, the excellent selectivity profile of A-366 has aided in the discovery of an important role for G9a/GLP in lineage maintenance of a subset of leukemias. Treatment of various leukemia cell lines in vitro resulted in marked differentiation and morphological changes of these tumors in the absence of cytotoxicity resulting in cytostasis. Furthermore, treament of MV4;11 flank xenografts with A-366 resulted in growth inhibition in vivo consistent with the profile of H3K9me2 reduction observed. In summary, A-366 is a novel and highly selective peptide-competitive inhibitor of G9a/GLP that has enabled the discovery of a role for G9a/GLP enzymatic activity in the epigenetic maintenance of a subset of leukemia cells. Citation Format: Jun Guo, Marina Pliushchev, Yupeng He, Debra Ferguson, Sujatha Jagadeeswaran, Andrew Petros, Chaohong Sun, Niru B. Soni, Bailin Shaw, Alla Korepanova, David Maag, Ramzi Sweis, Fritz G. Buchanan, Michael Michaelides, Alex Shoemaker, Chris Tse, Gary G. Chiang, William N. Pappano. Discovery of A-366, a novel small molecule inhibitor that uncovers an unappreciated role for G9a/GLP in the epigenetics of leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5532. doi:10.1158/1538-7445.AM2014-5532
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Reversible histone methylation is an emerging new target in the field of epigenetic regulation. Here, we review histone methyltransferases in light of their role in disease formation and with regard to the state of the art in drug discovery.
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Pulmonary arterial hypertension (PAH) is a multifactorial disease associated with the remodeling of pulmonary blood vessels. If left unaddressed, PAH can lead to right heart failure and even death. Multiple biological processes, such as smooth muscle proliferation, endothelial dysfunction, inflammation, and resistance to apoptosis, are associated with PAH. Increasing evidence suggests that epigenetic factors play an important role in PAH by regulating the chromatin structure and altering the expression of critical genes. For example, aberrant DNA methylation and histone modifications such as histone acetylation and methylation have been observed in patients with PAH and are linked to vascular remodeling and pulmonary vascular dysfunction. In this review article, we provide a comprehensive overview of the role of key epigenetic targets in PAH pathogenesis, including DNA methyltransferase (DNMT), ten-eleven translocation enzymes (TET), switch-independent 3A (SIN3A), enhancer of zeste homolog 2 (EZH2), histone deacetylase (HDAC), and bromodomain-containing protein 4 (BRD4). Finally, we discuss the potential of multi-omics integration to better understand the molecular signature and profile of PAH patients and how this approach can help identify personalized treatment approaches.
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Gastric cancer is one of the most common types of cancer and the second most common cause of cancer-related mortality worldwide. An increasing number of recent studies have confirmed that gastric cancer is a multistage pathological state that arises from environmental factors; dietary factors in particulary are considered to play an important role in the etiology of gastric cancer. Improper dietary habits are one of the primary concerns as they influence key molecular events associated with the onset of gastric carcinogenesis. In the field of genetics, anticancer research has mainly focused on the various genetic markers and genetic molecular mechanisms responsible for the development of this of this disease. Some of this research has proven to be very fruitful, providing insight into the possible mechamisms repsonsible for this disease and into possible treatment modalities. However, the mortality rate associated with gastric cancer remains relatively high. Thus, epigenetics has become a hot topic for research, whereby genetic markers are bypassed and this research is directed towards reversible epigenetic events, such as methylation and histone modifications that play a crucial role in carcinogenesis. The present review focuses on the epigenetic events which play an important role in the development and progression of this deadly disease, gastric cancer.
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Gastric cancer is a major health problem worldwide occupying most frequent causes of cancer-related mortality. In addition to genetic modifications, epigenetic alterations catalyzed by DNA methyltransferases (DNMTs) are a well-characterized epigenetic hallmark in gastric cancer. The reversible nature of epigenetic alterations and central role of DNA methylation in diverse biological processes provides an opportunity for using DNMT inhibitors to enhance the efficacy of chemotherapeutics. In this review, we discussed key factors or mechanisms such as SNPs, infections and genetic modifications that trigger DNMTs level modification in gastric cancer, and their potential roles in cancer progression. Finally, we focused on how inhibitors of the DNMTs can most effectively be used for the treatment of gastric cancer with multidrug resistance.
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Epigenetic regulation is a crucial component of DNA maintenance and cellular identity. As our understanding of the vast array of proteins that contribute to chromatin accessibility has advanced, the role of epigenetic remodelers in disease has become more apparent. G9a is a histone methyltransferase that contributes to immune cell differentiation and function, neuronal development, and has been implicated in diseases, including cancer. In melanoma, recurrent mutations and amplifications of G9a have led to its identification as a therapeutic target. The pathways that are regulated by G9a provide an insight into relevant biomarkers for patient stratification. Future work is aided by the breadth of literature on G9a function during normal differentiation and development, along with similarities to EZH2, another histone methyltransferase that forms a synthetic lethal relationship with members of the SWI/SNF complex in certain cancers. Here, we review the literature on G9a, its role in melanoma, and lessons from EZH2 inhibitor studies.
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