Copyright ©The Author(s) 2021.
World J Gastroenterol. Sep 28, 2021; 27(36): 6004-6024
Published online Sep 28, 2021. doi: 10.3748/wjg.v27.i36.6004
Table 1 Histone methyltransferases play a major role in pancreatic cancer
Function in pancreatic cancer
PRMTsPRMT1HRMT1L2, HMT2, ANM1H4R3me2aIncrease the β-catenin protein level; Methylate Gli1 at R597[44,54]
PRMT5HRMT1L5, SKB1, HSL7H3R2me2sSilence the expression of the tumor suppressor FBW7; Promote EMT via activating EGFR/ AKT/β-catenin signaling[45,56,188,189]
KMTsSMYD3ZNFN3A1, ZMYND1H4K5me3Affect the PC progression by regulating MMP-2; Potentiate Ras signaling through methylation of MAP3K2[62,64]
EZH2KMT6, WVS, ENX-1H3K27me3Suppress miR-139-5p expression by upregulating H3K27me3; Repress the E-cadherin by tri-methylation of H3K27[78,190]
Table 2 Histone demethylase that plays a major role in pancreatic cancer
Function in pancreatic cancer
KDM1KDM1ALSD1H3K4me1Promote the occurrence of cancer[83]
KDM1BLSD2, AOF1H3K4me2Related to tumor tissue apoptosis[84]
Jumonji CKDM2BNdy1, FBXL10, JHDM1BH3K4me3, H3K36me2Promote senescence of primary cells[109,110]
KDM3AJMJD1A, JHDM2AH3K9me2 (preferential), H3K9me1Regulate biological and pathological processes, including embryonic development, stem cell self-renewal and differentiation, genome integrity and tumorigenesis[191,192]
KDM4 familyKDM4AJMJD2AH3K36me3, H3K9me3Destruction of homologous recombination[120,138]
KDM4BJMJD2BH3K9me3Promote epithelial-mesenchymal transition[123]
KDM4DJMJD2DH3K9me2/me3Stimulates in vitro proliferation and cell survival, and plays a vital role in DNA double-strand break repair[193,194]
KDM5AJARID1A, RBBP2H3K4me2Promote the inhibition of active transcription and repair of DNA double-strand breaks[139,195]
KDM6 familyKDM6AUTXH3K27me2/me3The effect of KDM6A on PC tissue is currently unclear[196]
KDM6BJMJD3H3K27me2/me3Enhance the aggressiveness of cancer cells[176]
PHD finger and zinc finger protein familyKDM7AJHDM1DH3K9me2, H3K27me2May be related to the upregulation of E-cadherin gene expression[93]
Table 3 Different enzymes and plant homeodomain finger domain
Type of enzyme
Name of enzyme
PHD domain
Histone substrates
Histone demethylation enzymeKDM1B/LSD2PHDH3K4me2Unknown[25]
KDM4A-CTwo PHDUnknownUnknown[155,197]
KDM5APHD1Unmethylated H3K4 histone tailPHD1 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]
PHD2Unmodified H3K4Unknown[158]
PHD3H3K4me3PHD3 finger can recruit substrate and it relates to demethylation propagation along nucleosomes via a positive-feedback regulatory mechanism[151,199]
KDM5BPHD1H3K4me0PHD1 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]
PHD2Couldn’t bind to histoneUnknown[17]
PHD3H3K4me3/H3K4me0PHD3 finger detects H3K4me3, anchors at chromatin and spreads the transcriptionally inactive state
KDM5CPHD1H3K4PHD1 finger stabilizes the substrate peptide and helps to position the H3K4 in the JmjC finger exactly[162]
PHF8(KDM7subfamily)PHD1Suppressive marks on H3K9me2/me3 and H3K27me2/me3 and H4k20me2/me3PHD1 finger plays a significant role in PHF8 substrate recognition and helps to improve substrate affinity and specificity[164]
Histone methylation enzymeKMT2A, KMT2BPHD1UnknownPHD1 finger is necessary for a context-dependent regulation of holocomplex formation and implicated in tumor suppression[143]
PHD2UnknownPHD2 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
PHD3H3K4me3/me2Unclear, 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]
PHD4UnknownPHD4 finger mediates intramolecular interactions between the N-terminal and C-terminal fragments of KMT2A with PHD1, and improves its stability[143]
KMT2CEight PHD fingersUnknownThese fingers help KMT2C to recruit to its target genes correctly[30,146]
KMT2DSeven PHD fingersUnmodified histone H4 and asymmetrical H4R3me2These fingers are essential for methyltransferase activity of KMT2D and KMT2D-mediated differentiation[201]
KMT2EPHDH3K4me3PHD finger binds to H3K4me3 specially and facilitates the recruitment of KMT2E to active transcription chromatin regions[148,149,202]
Table 4 Inhibitors for the treatment of pancreatic cancer
Drug type
Drug name
Active site
Targeting tumors
Relating to histone methyltransferaseSMYD3 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 cavityBCI-121 is a competitive inhibitor significantly inhibits; SMYD3-substrate interaction and chromatin recruitmentIt inhibits cancer cell growth and accumulates during the cell cycle SHigh expression of SMYD3 protein in cancer cell lines (pancreatic cancer, lung, prostate and ovarian cancer)[173]
PRMT5 inhibitor EZP015556MTAP-It works for MTAP He and MTAP PDOA negative tumor MTAP (a commonly lost gene in pancreatic cancer)[174]
EZH2 inhibitor 3-Dazocycline A (DZNeP)It regulates EZH2 and H3K27me3 protein expressionDZNeP inhibit the activity of S-adenosine-L-homocysteine (AdoHcy) hydrolase, which reversely hydrolyzes AdoHcy to adenosine and homocysteine, thereby inhibiting histone methylationIt synergistically enhanced antiproliferative activity of gemcitabine and significantly increased apoptosis ratePancreatic ductal carcinoma[175]
Relating to histone demethylaseBET inhibitor JQ1 related to KDM6AReducing activity and p63 levels of MYC pathwaysGLI1 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 responseAltered KMT2C (MLL3)-KDM6A (UTX)- PRC2 regulating axisPancreatic ductal carcinoma[169,176,177]