Role of Histone Methyltransferase in Breast Cancer
Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman in Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Moreover, the role of G9a in gene repression studies has been studied predominantly by its histone methyltransferase activity; it is more clearly illustrated that G9a might play a role in active gene activation on certain specific conditions [100–102], that is markedly methyltransferase independent. In addition, this function mentioned above was clearly mapped in the N-protein terminal as 280 amino acids that present first in the protein chain as highly sufficient to promote the expression of the gene through acting as a scaffold to promote transcriptional co-activator recruitment including CARM1 and p300 [101,103]. At last, G9a is a protein with complexity that is highly involved in activating and repressing genes through specific but distinct mechanisms.
Cognition Enhancers
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
Neurotrophins (NTs) are the family of proteins that help in functioning, survival, and development of neurons. Levi-Montalcini and Cohen discovered the nerve growth factor (NGF) (the first NT) in 1950s. After 30 years, brain-derived neurotrophic factor (BDNF) was discovered which was followed by NT-3, NT-4, then central neurotrophic factor (CNF), and members of glial cell line neurotrophic factor family. The widely studied NT pertaining to restoration of synapse is BDNF. The BDNF messenger ribonucleic acid (mRNA) are reduced during AD (Murray et al., 1994; Phillips et al., 1991; Connor et al., 1997) and process of aging (Calabrese et al., 2013). Similarly, another receptor of BDNF was tropomyosin receptor kinase B (TrkB). Phosphorylated TrkB is down-regulated in aged rats (Calabrese et al., 2013). PKC phosphorylates co-activator associated arginine methyltransferase 1 (CARM1), which is a protein that methylates HuD (RNA binding protein) that enhances the expression and stability of NT-3, NGF, and BDNF. The expression of these proteins has displayed an increase in development of hippocampal neurons in the culture (Lim and Alkon, 2012). Therefore, BDNF can be increased by modulating the receptor of NT and NT mRNA pharmacologically.
Recent advances in targeting protein arginine methyltransferase enzymes in cancer therapy
Published in Expert Opinion on Therapeutic Targets, 2018
Emily Smith, Wei Zhou, Polina Shindiapina, Said Sif, Chenglong Li, Robert A. Baiocchi
PRMT4, also referred to as co-activator-associated arginine methyltransferase 1 (CARM1), was the first PRMT shown to coordinate transcriptional regulation [39]. By generating the H3R17me2a and H3R26me2a marks, CARM1 works with several other transcriptional factors including p53, NF-κB, peroxisome proliferator-activated receptor gamma, and c-Fos to regulate target gene expression [17]. Numerous instances of histone crosstalk have been linked to CARM1-associated marks. CBP/P300-driven acetylation of H3K18 converts H3 to an improved substrate for CARM1 and increases the rate of the methyltransferase reaction [40]. It is hypothesized that by neutralizing the positive charge of K18 the nucleophilic attack on the sulfur-methyl bond of SAM becomes more favorable [41]. It is also hypothesized that the H3R26me2a mark antagonizes methylation of H3K27 by the polycomb repressive complex-2 by preventing enzymatic activity, but not binding of the complex [42]. In addition to epigenetic regulation, CARM1 also methylates transcription factors to coordinate gene expression, splicing factors to couple transcription and splicing processes, as well as RNA polymerase II [43]. Mice with a CARM1 deletion illustrate the in vivo importance of this enzyme. Mouse embryos show defects in development of T lymphocytes, adipose tissue, chondrocytes, muscles, and lungs [44–47]. Newborn mice are smaller than wildtype counterparts and die shortly after birth [48].
Discovery and biological evaluation of novel CARM1/HDAC2 dual-targeting inhibitors with anti-prostate cancer agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Sudong Liang, Yifei Geng, Miao-Miao Niu, Yan Zhang, Weiping He, Jindong Li, Li Yang, Zhen Xu
Coactivator-associated arginine methyltransferase 1 (CARM1), also referred to as PRMT4 is a member of the protein arginine methyltransferases (PRMTs) family10. PRMTs transfer a methyl group from S-adenosyl-L-methionine (SAM) to the side chain of specific arginine residues of the substrate protein11. According to the location of methylation, PRMTs are classified into three categories: type I, II, and III12. CARM1 is one of the type I PRMTs and converts arginine into monomethyl arginine (MMA) and asymmetric dimethylarginine (ADMA)10,13. CARM1 can modify the methylation of histone H3R17 and H3R26, as well as other chromatin-associated nonhistone proteins, like chromatin remodelling factor BAF155, and RNA-binding protein HuR14–16. Therefore, CARM1 is frequently involved in diverse biological processes, such as DNA repair, transcriptional coactivation, mRNA splicing, and autophagy17–20. The aberrant expression of CARM1 is related to PCa21,22. CARM1 is essential in the oncogenic growth of prostate cancer, and overexpression of CARM1 in PCa correlates with androgen signalling, cell cycle, and EMT regulators21. Importantly, dysregulation of CARM1 is also implicate in other tumours like breast cancer, pancreatic cancer, and non-small cell lung cancer (NSCLC)23–25. In the past few years, several CARM1 inhibitors have been reported, most of which are small molecule inhibitors containing the alanine amide moiety and ethylenediamine side chain, but they showed low cellular activity and poor selectivity against other type I PRMTs26–28. Since then, great efforts have been made to find inhibitors with high in vivo activity, such as EZM2302 and TP-064 (Figure 1), which were discovered with potent and selective in vivo activities in human multiple myeloma models29–31. However, none of the CARM1 inhibitors have been approved yet.
Related Knowledge Centers
- Chromatin REModeling
- Enzyme
- Nicotinamide Adenine Dinucleotide Phosphate
- Pancreatic Cancer
- Arginine
- S-Adenosyl Methionine
- S-Adenosyl-L-Homocysteine
- Coactivator
- Nuclear Receptor Coactivator 1
- Nuclear Receptor Coactivator 3