Histone methylation in pancreatic cancer and its clinical implications

Table 1 Histone methyltransferases play a major role in pancreatic cancer

Family	Subfamily	Alias	Site	Function in pancreatic cancer
PRMTs	PRMT1	HRMT1L2, HMT2, ANM1	H4R3me2a	Increase the β-catenin protein level; Methylate Gli1 at R597[44,54]
	PRMT5	HRMT1L5, SKB1, HSL7	H3R2me2s	Silence the expression of the tumor suppressor FBW7; Promote EMT via activating EGFR/ AKT/β-catenin signaling[45,56,188,189]
KMTs	SMYD3	ZNFN3A1, ZMYND1	H4K5me3	Affect the PC progression by regulating MMP-2; Potentiate Ras signaling through methylation of MAP3K2[62,64]
	EZH2	KMT6, WVS, ENX-1	H3K27me3	Suppress miR-139-5p expression by upregulating H3K27me3; Repress the E-cadherin by tri-methylation of H3K27[78,190]

All current research on reprogramming histone methyltransferases that play a role in pancreatic cancer. EMT: Epithelial-mesenchymal transition; FBW7: F-Box and WD repeat domain containing 7; KMTs: Histone lysine methyltransferases; PC: Pancreatic cancer; PRMTs: Protein arginine N-methyltransferases.

Table 2 Histone demethylase that plays a major role in pancreatic cancer

Family	Subfamily		Alias	Site	Function in pancreatic cancer
KDM1	KDM1A		LSD1	H3K4me1	Promote the occurrence of cancer[83]
	KDM1B		LSD2, AOF1	H3K4me2	Related to tumor tissue apoptosis[84]
Jumonji C	KDM2B		Ndy1, FBXL10, JHDM1B	H3K4me3, H3K36me2	Promote senescence of primary cells[109,110]
	KDM3A		JMJD1A, JHDM2A	H3K9me2 (preferential), H3K9me1	Regulate biological and pathological processes, including embryonic development, stem cell self-renewal and differentiation, genome integrity and tumorigenesis[191,192]
	KDM4 family	KDM4A	JMJD2A	H3K36me3, H3K9me3	Destruction of homologous recombination[120,138]
		KDM4B	JMJD2B	H3K9me3	Promote epithelial-mesenchymal transition[123]
		KDM4D	JMJD2D	H3K9me2/me3	Stimulates in vitro proliferation and cell survival, and plays a vital role in DNA double-strand break repair[193,194]
	KDM5A		JARID1A, RBBP2	H3K4me2	Promote the inhibition of active transcription and repair of DNA double-strand breaks[139,195]
	KDM6 family	KDM6A	UTX	H3K27me2/me3	The effect of KDM6A on PC tissue is currently unclear[196]
		KDM6B	JMJD3	H3K27me2/me3	Enhance the aggressiveness of cancer cells[176]
	PHD finger and zinc finger protein family	KDM7A	JHDM1D	H3K9me2, H3K27me2	May be related to the upregulation of E-cadherin gene expression[93]

All current research on reprogramming histone demethylases that play a role in pancreatic cancer. The table is sorted by family. PC: Pancreatic cancer; PHD: Plant homeodomain.

Table 3 Different enzymes and plant homeodomain finger domain

Type of enzyme	Name of enzyme	PHD domain	Histone substrates	Function
Histone demethylation enzyme	KDM1B/LSD2	PHD	H3K4me2	Unknown[25]
	KDM2A	PHD	H3K36me2/me1	Unknown[150]
	KDM4A-C	Two PHD	Unknown	Unknown[155,197]
	KDM5A	PHD1	Unmethylated H3K4 histone tail	PHD1 finger by H3 N-terminal tail peptides stabilizes binding of the substrate to the catalytic finger and improves the catalytic efficiency of demethylation[198,199]
		PHD2	Unmodified H3K4	Unknown[158]
		PHD3	H3K4me3	PHD3 finger can recruit substrate and it relates to demethylation propagation along nucleosomes via a positive-feedback regulatory mechanism[151,199]
	KDM5B	PHD1	H3K4me0	PHD1 finger recognizes the N-terminus of histone H3, provides an anchoring mechanism for KDM5B and PHD1-H3K4me0 is interaction is important for inhibition of migration[17]
		PHD2	Couldn’t bind to histone	Unknown[17]
		PHD3	H3K4me3/H3K4me0	PHD3 finger detects H3K4me3, anchors at chromatin and spreads the transcriptionally inactive state
	KDM5C	PHD1	H3K4	PHD1 finger stabilizes the substrate peptide and helps to position the H3K4 in the JmjC finger exactly[162]
	PHF8(KDM7subfamily)	PHD1	Suppressive marks on H3K9me2/me3 and H3K27me2/me3 and H4k20me2/me3	PHD1 finger plays a significant role in PHF8 substrate recognition and helps to improve substrate affinity and specificity[164]
Histone methylation enzyme	KMT2A, KMT2B	PHD1	Unknown	PHD1 finger is necessary for a context-dependent regulation of holocomplex formation and implicated in tumor suppression[143]
		PHD2	Unknown	PHD2 finger shows the E3 ubiquitin ligase activity and involve in homo-dimerization[144,200]. Mutation in PHD2 will enhance transactivation ability and help to recruit target gene promoters
		PHD3	H3K4me3/me2	Unclear, one possibility is binding of H3K4me3 by PHD3 is necessary for the transcription-promoting effects of KMT2A/2B, another is to set a broad, methylated chromatin finger[145]
		PHD4	Unknown	PHD4 finger mediates intramolecular interactions between the N-terminal and C-terminal fragments of KMT2A with PHD1, and improves its stability[143]
	KMT2C	Eight PHD fingers	Unknown	These fingers help KMT2C to recruit to its target genes correctly[30,146]
	KMT2D	Seven PHD fingers	Unmodified histone H4 and asymmetrical H4R3me2	These fingers are essential for methyltransferase activity of KMT2D and KMT2D-mediated differentiation[201]
	KMT2E	PHD	H3K4me3	PHD finger binds to H3K4me3 specially and facilitates the recruitment of KMT2E to active transcription chromatin regions[148,149,202]

All current research on the regulation of writers and erasers by plant homeodomain domain. “Unknown” means that the corresponding literature was not mentioned. This table is sorted by types and subfamilies of enzymes. JmjC: Jumonji C; KMT: Histone lysine methyltransferase; PHD: Plant homeodomain.

Table 4 Inhibitors for the treatment of pancreatic cancer

Drug type	Drug name	Active site	Mechanism	Effect	Targeting tumors
Relating to histone methyltransferase	SMYD3 inhibitor piperidine-4-formamide-acetylaniline compound (BCI-121)	It competes with histones to bind SMYD3, binding sites are formed within the SET and post-SET fingers and contained in a deep and narrow substrate binding cavity	BCI-121 is a competitive inhibitor significantly inhibits; SMYD3-substrate interaction and chromatin recruitment	It inhibits cancer cell growth and accumulates during the cell cycle S	High expression of SMYD3 protein in cancer cell lines (pancreatic cancer, lung, prostate and ovarian cancer)[173]
	PRMT5 inhibitor EZP015556	MTAP	-	It works for MTAP He and MTAP PDO	A negative tumor MTAP (a commonly lost gene in pancreatic cancer)[174]
	EZH2 inhibitor 3-Dazocycline A (DZNeP)	It regulates EZH2 and H3K27me3 protein expression	DZNeP inhibit the activity of S-adenosine-L-homocysteine (AdoHcy) hydrolase, which reversely hydrolyzes AdoHcy to adenosine and homocysteine, thereby inhibiting histone methylation	It synergistically enhanced antiproliferative activity of gemcitabine and significantly increased apoptosis rate	Pancreatic ductal carcinoma[175]
Relating to histone demethylase	BET inhibitor JQ1 related to KDM6A	Reducing activity and p63 levels of MYC pathways	GLI1 is the main target gene of the Hh pathway JQ1 reduces the mRNA and protein levels of primary human CAFs. TGF-β is an interstitial activator that JQ1 its induced response	Altered KMT2C (MLL3)-KDM6A (UTX)- PRC2 regulating axis	Pancreatic ductal carcinoma[169,176,177]

All current research on inhibitors for the treatment of pancreatic cancer developed based on histone methylation modification. “-” means that the content does not exist here. This table is sorted according to the correlation with histone methyltransferases and demethylases. CAF: Cancer-associated fibroblast; KMT: Histone lysine methyltransferases; PDO: Patient-derived organoid; PRC2: Polycomb repressive complex 2; TGF-β: Transforming growth factor β.