Page 7 - J. Chromatin remodeling and epigenetics

Immune regulation of mammalian polycomb repressor
and the relationship between its structural heterogeneity

Seok-jin Kang, Taehoon Chun
Department of Biotechnology, College of Life Sciences and Biotechnology,
Korea University, Seoul, 02841, Republic of Korea

BACKGROUND AIM
Alteration of chromatin structure is one of the main methods for modifying cell phenotypes by regulating DNA replication This study is to let people know that there are many
and transcription of mRNA. Methylation of DNA change the structure of chromatin, but addition of chemical moieties such combinatorial number of cases of polycomb groups and show
as methylation, acetylation, ubiquitination, sumoylation to histone tails also alter the 3D structure of chromatin. The them in 3D structure to better understand the nature of
enzymes that acetylate, methylate, ubiquitinate and phosphorylate certain amino acid residues of histone tails have been polycombs. Polycomb proteins play critical roles in cell
identified to define the biological function of each epigenetic enzymes. Recent studies have provided proofs that histone differentiation, proliferation, senescence and so on.
modification plays a important role in cell fates such as differentiation, proliferation, senescence and carcinogenesis.
Different combination of polycomb group engage in different
Polycomb group proteins (PcG) were first identified in fruit flies. Their sequences are well conserved from invertebrates to stages of cell differentiation. In this study, we gathered the
mammals. The proteins can act as repressor of transcription by suppressing the transcription of specific mRNA through information about different polycomb group protein associated
trimethylation or monoubiquitination of histone H3 and H2A. To begin and maintain chromatin modification, two distinct with hematopoiesis differentiation.
protein complexes, PRC1 and PRC2, work in coordination with each other. PRC2 exhibits methyltransferase activity to
add methyl groups to specific amino acid residues of histone H3, while PRC1 exhibits E3 ubiquitin ligase activity to As function of polycomb proteins are revealed, studies to treat
modify the structure of histone H2A. PcG complexes show structural plasticity because PcG subunit proteins exist in human disease by regulating polycomb group protein are in the
several paralogs. In particular, more than 100 different types of PRC1 complexes may exist based on a simple pipeline. We summarized clinical trials targeting polycomb group
proteins to treat human cancer.
combinatorial algorithm.
RESULTS
Figure 1
Figure 1 The repressive mechanism of specific mRNA transcription by PcG proteins
through the modification of chromatin structure.
Schematic representation of transcriptional repression by PcG proteins according to the
‘hierarchical repressive model’ (a) and the ‘reverse hierarchical repressive model’ (b). a
Core subunits of PRC2 (EED, EZH, SUZ12, RBBP) recognize and repress a target locus
by introducing H3K27me3. The CBX subunit of canonical PRC1 (PRC1.2 and PRC1.4)
then recognizes the H3K27me3 tag, and canonical PRC1 further represses the target
locus by introducing H2AK119. b The KDM2B subunit of noncanonical PRC1 (PRC1.1)
recognizes CpG, and PRC1.1 represses the target locus by introducing H2AK119. The
JARID2 subunit of PRC2.2 then recognizes the H2AK119 tag, and PRC2.2 further
represses the target locus by introducing H3K27me3.

Figure 2

Figure 2 Functional contribution of PcG proteins during immune cell differentiation.
Schematic representation of particular PRC2 or PRC1 complexes involved in hematopoiesis
according to the ‘hierarchical repressive model’.

Target polycomb subunit Agent Mode of action NCT ID Phase Target tumor types status
EZH2 Tazemetostat (EPZ-6438) S-adenosyl- L-methionine (SAM) competitive inhibitor NCT02875548 II Diffuse large B cell lymphoma Recruiting
NCT02601950 II INI (hSNF5; SMARCB1)-negative Recruiting
tumor and relapsed/refractory
synovial sarcoma
NCT01897571 I/II Advanced solid tumor and Active, not
B cell lymphoma recruiting
NCT02601937 I INI (hSNF5; SMARCB1)-negative Recruiting
tumor and synovial sarcoma
NCT02860286 II Malignant mesothelioma Completed
NCT03213665 II Relapsed/refractory advanced Recruiting
solid tumor and non-
Hodgkin’s lymphoma
NCT02889523 Ib/II Diffuse large B cell lymphoma Suspended
NCT03217253 I Metastatic or unresectable solid Active,not
tumor recruiting
NCT03348631 II Recurrent ovarian cancer Suspended We summarizes the inhibitors of PcG proteins applied to clinical trials in hematopoietic
GSK2816126 SAM competitive inhibitor NCT02082977 I Relapsed/refractory diffuse large Terminated
B cell lymphoma and transformed follicular malignancies and other types of tumors. Major groups of inhibitors target EZH enzyme
lymphoma
CPI-1205 SAM competitive inhibitor NCT02395601 I B cell lymphoma Completed
CPI-0209 Second generation inhibitor of EZH2 NCT04104776 I/II Advanced solid tumor Recruiting activity. Most EZH2 inhibitors undergoing clinical trials compete with SAM for binding to the
PF-06821497 SAM competitive inhibitor NCT03460977 I Relapsed/refractory small cell Recruiting SET domain. Among the competitive inhibitors of EZH, tazemetostat (EPZ- 6438), an orally
lung cancer,castrationresistant
prostate cancer
SHR2554 SAM competitive inhibitor NCT03603951 I Relapsed/refractory mature Recruiting administered small chemical, has been applied to a broad range of malignant cell types,
lymphoid neoplasm including lymphoma, sarcoma, mesothelioma, ovarian cancers and advanced solid tumors.
EZH1 and EZH2 DS-3201b (Valemetostat SAM competitive inhibitor NCT04102150 II Relapsed/refractory adult T cell Recruiting
leukemia/lymphoma Other inhibitors of PcG proteins that are currently undergoing clinical trials target EED and
EED MAK683 Binds to EED and change overall shape of PRC2 NCT02900651 I/II Diffuse large B cell lymphoma Recruiting
BMI1 PTC-596 Phosphorylation of BMI-1 at two N-terminal sites NCT03605550 Ib High grade glioma and diffuse Recruiting BMI-1 activity. MAK683 is an allosteric EED inhibitor that drives conformational changes in
which leads to the degradation of BMI-1 intrinsic
NCT03206645 I Ovarian cancer Recruiting the H3K27me3-binding pocket of EED upon binding.
NCT02404480 I Advanced solid cancer Completed
NCT03761095 I Leiomyosarcoma Recruiting
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