H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

Abstract

Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

Inhibitors of Protein Methyltransferases and Demethylases

“…NSD1, MMSET, WHSC1L1, ASH1L, and SETD2 have closely related catalytic SET domains and show H3K36 methylation specificity in vitro and in vivo, while SMYD2, SETMAR, and SETD3 have less similarity in their SET domains with less well-characterized activities toward H3K36. 203 For example, SMYD2 (also known as KMT3C) was reported to methylate H3K4 as well as H3K36 in vitro, 152 and SMYD2-mediated H3K36me2 was reported to repress the transcription of pro-inflammatory cytokines IL-6 and TNF-α in macrophages. 204 However, inhibition or knockdown of SMYD2 does not affect global levels of mono-, di-, or trimethylation of H3K4 or H3K36, and most of SMYD2 is found in the cytoplasm, suggesting minimal SMYD2 activity on chromatin.…”

Melatonin disturbs SUMOylation‐mediated crosstalk between c‐Myc and nestin via MT1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells

“…In addition, mono‐methylation of H3K9, H3K27, and H3K79 and dimethylation of H3K79 are gene transcription activator, while trimethylation of H3K79 is facultive . Also, H3K4 me3 and H3K4 me2 marks are known to bind directly to transcriptional activators and also H3K36 methyltransferases are considered as cancer drug targets …”

“…31,32 Also, H3K4 me3 and H3K4 me2 marks are known to bind directly to transcriptional activators 33,34 and also H3K36 methyltransferases are considered as cancer drug targets. 32,35 Emerging evidences revealed that small ubiquitinlike modifiers (SUMOs) such as SUMO-1, SUMO-2, and SUMO-3 in mammalian systems 36 are found covalently attached to more than 50 proteins including p53, androgen receptor, IkBα, c-jun, histone deacetylases (HDACs), and other proteins 37 with major functions of SUMOylation, cytoplasmic nuclear transport, transcripton, and DNA repair. 38 Although paclitaxel, so-called taxol, has been used for chemotherapy in several cancers including ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer, and pancreatic cancer and cancer stem cells, 39 its resistance in stem cells 40,41 and side effects 42,43 are still hot issues for effective cancer therapy.…”

Lysine-specific demethylase 2A gene expression in clear cell renal cell carcinoma and its clinical significance

“…Histone lysine methylation was regarded as a central modification for the post-transcriptional regulation of chromosome structure and DNA replication, repair, and transcription procedure [14], and was relevant to the activation or silencing of gene expression [15]. KDM2A can specifically catalyze the demethylation of histone H3K36, which is a conserved epigenetic marker influencing gene transcription, alternative splicing, and DNA repair [16,17]. During cell mitosis, KDM2A plays a role in maintaining genomic stability and centromeric integrity [11].…”