Novel insights into histone lysine methyltransferases in cancer therapy:From epigenetic regulation to selective drugs

The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.

Histone methyltransferases and demethylases:regulators in balancing osteogenic and adipogenic differentiation of mesenchymal stem cells

Mesenchymal stem cells （MSCs） are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su（var）3-9, enhancer-of-zeste, trithorax （SET） domain-containing family and the Jumonji C （JmjC） domain-containing family represent the major histone lysine methyltransferases （KMTs） and histone lysine demethylases （KDMs）, respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containine KMTs and JmiC domain-containinlz KDMs balance the osteogenic and adipogenic differentiation of MSCs.

Cellular functions of MLL/SET-family histone H3 lysine 4 methyltransferase components

The MLL/SET family of histone H3 lysine 4 methyltransferases form enzyme complexes with core subunits ASH2L, WDR5, RbBP5, and DPY-30 （often abbreviated WRAD）, and are responsible for global histone H3 iysine 4 methylation, a hallmark of actively transcribed chromatin in mammalian cells. Accordingly, the function of these proteins is required for a wide variety of processes including stem cell differentiation, cell growth and division, body segmentation, and hematopoiesis. While most work on MLL-WRAD has focused on the function this core complex in histone methylation, recent studies indicate that MLL-WRAD proteins interact with a variety of other proteins and IncRNAs and can localize to cellular organelles beyond the nucleus. In this review, we focus on the recently described activities and interacting partners of MLL-WRAD both inside and outside the nucleus.

Structure of human lysine methyltransferase Smyd2 reveals insights into the substrate divergence in Smyd proteins

The SET-and myeloid-Nervy-DEAF-1(MYND)-domain containing(Smyd)lysine methyltransferases 1–3 share relatively high sequence similarity but exhibit divergence in the substrate specificity.Here we report the crystal structure of the full-length human Smyd2 in complex with S-adenosyl-L-homocysteine(AdoHcy).Although the Smyd1–3 enzymes are similar in the overall structure,detailed comparisons demonstrate that they differ substantially in the potential substrate-binding site.The binding site of Smyd3 consists mainly of a deep and narrow pocket,while those of Smyd1 and Smyd2 consist of a comparable pocket and a long groove.In addition,Smyd2,which has lysine methyltransferase activity on histone H3-lysine 36,exhibits substantial differences in the wall of the substrate-binding pocket compared with those of Smyd1 and Smyd3 which have activity specifically on histone H3-lysine 4.The differences in the substrate-binding site might account for the observed divergence in the specificity and methylation state of the substrates.Further modeling study of Smyd2 in complex with a p53 peptide indicates that mono-methylation of p53-Lys372 might result in steric conflict of the methyl group with the surrounding residues of Smyd2,providing a structural explanation for the inhibitory effect of the SET7/9-mediated mono-methylation of p53-Lys372 on the Smyd2-mediated methylation of p53-Lys370.