HMTase

HMTase (Histone methyltransferases) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl teams to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at precise lysine or arginine residues on histones H3 and H4. Two major kinds of histone methyltranferases exist, lysine-precise and arginine-precise.

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CARM1-IN-1
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1035227-43-0
AZ505
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1035227-44-1
1035227-44-1
1158279-20-9
HLCL-61 hydrochloride
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UNC0224
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UNC-0638
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1271738-59-0
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1271738-62-5
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UNC 669
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1320288-17-2
UNC0646
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UNC-0631
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1338466-77-5
EPZ004777
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1374601-40-7
BRD4770
1374601-40-7
1380288-87-8
EPZ-5676
1380288-87-8

Background


An overview of HMTase

Histone-modifying enzymes, including histone methyltransferases (HMTase), histone acetyltransferases, histone deacetylase, ubiquitin ligases, and other specific kinases phosphorylating serine residues on histones, are believed to control the post-translation epigenetic modifications of histones in order to control the gene expression. In the 1960s, Allfrey and Murray first described histone methylation modification. Histone methylation refers to methylation at the N-terminal tail of histones, which transfers the methyl group on S-adenosylmethionine (AdoMet) to the target under the action of HMTase. The process involves the amino group at the end of a protein lysine residue or the muscle base at the end of an arginine residue. Histone methylation is catalyzed by HMTase, consisting of a class of proteins containing the SET domain. The abnormal expression of histone methylation and its regulator HTMase is closely related to the occurrence of various tumors. Therefore, targeting HMTase and reversing abnormal histone methylation levels are considered as new approaches to tumor therapy.

Major types of HMTase

To date, more than 60 types of HTMase have been discovered and most of them have been found to play critical roles in cell differentiation, gene regulation, DNA recombination and damage repair, including dozens of histone lysine methyltransferases (HKMTs) and histone/protein arginine methyltransferases (PRMTs).

Inhibition of HMTase

A large number of clinical data indicate that abnormalities in histone methylation modification are closely related to tumorigenesis, especially in the presence of multiple histone methyltransferases in tumors. Therefore, histone methyltransferase has been regarded as another new target for the development of anti-tumor drugs. At present, some compounds have been designed and found to exert anti-tumor effects by inhibiting HMTase. For example, inhibitors of histone lysine methyltransferase mainly include EPZ005687, EPZ-6438, GlaxoSmithKine, etc. These inhibitors reduce the level of H3K27me3 in cells by inhibiting the function of histone methyltransferase, and finally make EZH2 the target gene (mostly a tumor suppressor gene) is activated to exert its anti-tumor effect.

HMTase and diseases

The researchers found that a variety of histone methyltransferases were abnormal in tumors. For example, some genes in histone lysine methyltransferase are highly expressed in many tumors such as prostate cancer, breast cancer, and bladder cancer, and have been used as molecular markers for prognosis of breast cancer and metastatic prostate cancer, and Mutations in genes are closely related to the development of lymphoma. The histone methyltransferase NSD2 can indirectly activate myeloma-associated oncogenes and promote myeloma.

References:

1. Zhou, V. W., Goren, A. & Bernstein, B. E. Charting histone modifications and the functional organization of mammalian genomes. Nature Reviews Genetics 12, 7-18, doi:10.1038/nrg2905 (2011).

2. Liu, Q. & Wang, M. W. Histone lysine methyltransferases as anti-cancer targets for drug discovery. Acta Pharmacologica Sinica 37, 1273-1280, doi:10.1038/aps.2016.64 (2016).

3. Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nature Reviews Genetics 13, 343-357, doi:10.1038/nrg3173 (2012).