Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1617, USA.
Department of Chemistry, Colorado State University, Fort Collins, CO 80523-1872, USA.
Molecules. 2023 Feb 20;28(4):2000. doi: 10.3390/molecules28042000.
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.
全面了解表观遗传变化在基因表达中的机制对于与赖氨酸甲基转移酶 SMYD 家族相关疾病的临床管理至关重要。已知的五种 SMYD 酶催化供体甲基从 S-腺苷甲硫氨酸（SAM）转移到组蛋白和非组蛋白底物上的特定赖氨酸。SMYDs 家族成员具有不同的组织分布和组织特异性功能，包括调节发育、细胞分化和胚胎发生。与 SMYDs 相关的疾病包括心脏离子通道形成所需的 SMYD1 基因转录受到抑制导致心力衰竭，食管鳞状细胞癌（ESCC）或与 p53 相关的癌症中 SMYD2 过表达，以及超过 14 种癌症（包括乳腺癌、结肠癌、前列腺癌、肺癌和胰腺癌）中 SMYD3 过表达与预后不良相关。鉴于表观遗传学在各种病理学中的重要性，表观遗传抑制剂的开发引起了制药行业的极大关注。抑制剂的药理开发涉及鉴定调节 SMYD SET（变异性抑制物、增强子、Trithorax）和 MYND（骨髓神经缺失-DEAF1）结构域功能的分子，这一过程得益于可用的 SMYD1、SMYD2 和 SMYD3 的 X 射线结构。已经报道了针对 SMYD2 和 SMYD3 酶的潜在药物制剂的重要先导化合物，并且已经开发了六种用于治疗骨髓增生异常综合征（Vidaza、Dacogen）、皮肤 T 细胞淋巴瘤（Zoinza、Isrodax）和外周 T 细胞淋巴瘤（Beleodag、Epidaza）的药物的表观遗传抑制剂。最近证明的 SMYD 组蛋白甲基化逆转表明，逆转癌症组织中 SMYDs 的表观遗传效应可能是药理学开发的理想目标。
