암 차단을 위한 천연 화합물로 후성유전학적 '리더' 표적화

2020

https://www.jcpjournal.org/journal/view.html?volume=25&number=4&spage=189 

Targeting Epigenetic ‘Readers’ with Natural Compounds for Cancer Interception

Targeting Epigenetic ‘Readers’ with Natural Compounds for Cancer Interception

Table 1 . Epigenetic reader modules and the histone marks recognized

ModificationResidueFamilyMember

Acetylation	Lysine	BRD	BRD 2/3/4/T/7/9
Methylation	Lysine	CRDs	MORF, MRG15
		Tudor domains	MBT, PHF1/19, TDRD7
		PWWP domains	BRPF1, NSD1-3
		Ankyrin repeats	GLP/G9a
	Arginine	Tudor domains	WDR5, TDRD3, SMN1
Phosphorylation	Serine	14-3-3 proteins BRCT domain	14-3-3β/γ/η/ε/µ
	Threonine	BIR domain	XRCC1, NBS1, BARD1
	Tyrosine	PTB domain
Ubiquitination	Lysine		53BP1
ADP-ribosylation	Glutamate	Macrodomains	RNF146
	Arginine	PBZ	APLF, CHFR
	Glutamate	WWE domain

BRD, bromodomain; CRD, chromodomain; PWWP, Pro-Trp-Trp-Pro; MORF, monocytic leukemia zinc finger protein-related factor; MRG15, MORF4-related gene on chromosome 15; MBT, malignant brain tumor; PHF, plant homeodomain (PHD) finger; TDRD3/7, Tudor domain containing proteins 3 and 7; BRPF1, BRD and PHD finger-containing protein 1; NSD1-3, nuclear receptor binding SET domain proteins 1-3; GLP, G9a-like protein; WDR5, WD repeat domain 5; SMN1, survival of motor neuron 1; BRCT, BRCA1 C terminus; BIR, baculovirus IAP repeat; XRCC1, X-ray repair cross complementing 1; NBS1, Nijmegen breakage syndrome 1; BARD1, BRCA1 associated RING domain 1; PTB, phosphotyrosine-binding; 53BP1, tumor suppressor p53-binding protein 1; PBZ, PAR-binding zinc finger; WWE, Trp-Trp-Glu; RNF146, RING finger protein 146; APLF, aprataxin and PNKP like factor; CHFR, checkpoint with forkhead and RING finger domains (Adapted from Catia et al., 2019 [26]).

 

Fig. 1.

 

Fig. 1. Bromodomain (BRD)-containing proteins and gene regulation. 

(A) BRD-containing proteins are frequently found in chromatin-remodeling complexes. For example, bromodomain adjacent to zinc finger domain (BAZ) proteins BAZ1A and BAZ2A promote chromatin compaction that leads to gene silencing. Other BRD-containing proteins promote chromatin decompaction, thus enhancing gene transcription. Examples include Switch/sucrose non-fermenting-related, matrix-associated, actin-dependent regulator of chromatin subfamily A members 2 and 4 (SMARCA2/4) and BAZ1B; cat eye syndrome critical region protein 2 (CECR2); BRD and PHD finger-containing transcription factor (BPTF); and ATPase family AAA domain-containing protein 2 (ATAD2). (B) BRD-containing proteins engage as bi-functional reader-writers in the acetylation and methylation of histones. They include acetyltransferases CREB-binding protein (CREBBP) and E1A-associated protein p300 (EP300), methyltransferases mixed-lineage leukaemia (MLL) and absent small and homeotic disks protein 1-like (ASH1L), or are part of larger histone-modifying complexes that include GCN5-like 2 (GCN5L2; also known as KAT2A), P300/CBP-associated factor (PCAF), BRD-containing protein 8 (BRD8) and the BRD and PHD finger-containing proteins (BRPFs), BRPF1, BRPF2 and BRPF3. (C) BRD-containing proteins can serve important roles in transcription by functioning as histone-recognizing scaffolds that promote the assembly of transcriptional complexes. For example, BRD and extraterminal (BET) proteins recruit components of the transcriptional machinery that positively regulate growth-promoting genes. Box: several natural compounds, including resveratrol and naringenin, are known BET inhibitors. Another BRD-containing protein, transcription initiation factor TFIID subunit 1 (TAF1), promotes transcription initiation. (D) BRD-containing speckled protein (SP) family members, zinc-finger MYND domain-containing protein 8 (ZMYND8), tripeptide motif-containing 24 (TRIM24) and TRIM33 can serve as transcriptional coregulators, while BRD-containing protein TRIM28 can act as a corepressor. TFs, transcription factors. 

Table 2 . Natural compounds targeting epigenetic ‘reader’ domains

Name & structureOriginTargetReference

Naringenin triacetate		Citrus aurantium (bitter orange)	BRD4	104
3-O-acetylpinobanksin		Black poplar tree
Kaempferol tetracetate		Cudrania tricuspidata (mandarin melonberry)
Resveratrol		Peanuts, berries, grape skin, apples	BRD4	112
Isoliquiritigenin		Glycyrrhiza glabra (licorice plant)	BRD4	113
Amentoflavone		Ginkgo biloba, Hypericum perforatum (St. John’s Wort), Biophytum sensitivum, Nandina domestica (sacred bamboo)	BRD4	102
Fisetin		Cucumber, onion, strawberry, apple
Aristoyagonine		Sarcocapnos enneaphylla	BRD4	125
α-Viniferin		Caragana sinica, camphor tree, Astilbe grandis	BRD4	134
Euscaphic acid		Plectranthus amboinicus (French thyme, Cuban oregano, Indian mint), Ziziphus jujuba (red date)
Magnolol		Magnolia tree	BRD9	135
Colchicine	Colchiceine	Colchicum speciosum (autumn crocus)	BRD4	126
Terrein		Mangrove-derived Streptomyces sp. SZ-A15	BRD4	136
4-oxo-Staurosporine		Marine-derived Streptomyces sp. NB-A22	BRD4	130
3,11α,12β,13β,6-pentahydroxy-11,12-dihydroperylen-6(13H)-one		Marine fungi: Alternaria sp. NH-F6	BRD4	137
5-hydroxymethyl-furan-2-carboxylic acid		Marine fungi: Phoma sp. CZD-F11, Aspergillus sp. CZD-F18	BRD4	138
4-hydroxymethyl catechol		Marine fungi: Phoma sp. CZD-F11, Aspergillus sp. CZD-F18
12-hydroxy-verruculogen TR-2	Fumitremorgin B	Penicillium sp. DT-F29 with Bacillus sp. B31	BRD4	131

**************************************************************************************