m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03049
 [1]
Histone modification H3K18la LDHA YTHDF2 Direct Enhancement m6A modification TP53 TP53 YTHDF2 : m6A sites
m6A Modification:
m6A Regulator YTH domain-containing family protein 2 (YTHDF2) READER
 Regulator Info 
m6A Target Cellular tumor antigen p53 (TP53/p53)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Lactate dehydrogenase A (LDHA) WRITER View Details
Regulated Target Histone H3 lysine 18 lactylation (H3K18la) View Details
Downstream Gene YTHDF2 View Details
Crosstalk Relationship Histone modification  →  m6A Enhancement
Crosstalk Mechanism histone modification directly impacts m6A modification through modulating the level of m6A regulator
Crosstalk Summary Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, LDHA/LDHB-mediated Histone H3 lysine 18 lactylation (H3K18la) contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and Cellular tumor antigen p53 (TP53/p53) mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma.
Responsed Disease Melanoma of uvea ICD-11: 2D0Y
 Disease Info 
In-vitro Model
 92-1 [Human uveal melanoma] Uveal melanoma Homo sapiens CVCL_8607
MuM-2B Uveal melanoma Homo sapiens CVCL_3447
OCM-1 Amelanotic melanoma Homo sapiens CVCL_6934
Mel290 Uveal melanoma Homo sapiens CVCL_C304
OMM-1 Uveal melanoma Homo sapiens CVCL_6939
CRMM-1 Conjunctival melanoma Homo sapiens CVCL_M593
CRMM-2 Conjunctival melanoma Homo sapiens CVCL_M594
CM2005.1 Conjunctival melanoma Homo sapiens CVCL_M592
PIG1 Normal Homo sapiens CVCL_S410
HEK293T Normal Homo sapiens CVCL_0063
In-vivo Model Briefly, nude mice were anesthetized by intraperitoneal injection of a ketamine (final concentration: 10 mg/mL) and xylazine (final concentration: 1 mg/mL) mixture (0.01 mL/g mouse weight). Then, the mouse sclera was pre-perforated using a sharp 30-gauge injection needle. Ocular melanoma cells (5 × 105) were injected through the hole made in the choroid by a 33-gauge blunt-end microinjection needle (7803-05, Hamilton, Reno, NV, USA). Then, the infected eyes were treated with ophthalmic bacitracin ointment. All animal experiments were approved by the Animal Care and Use Committee at Shanghai Jiao Tong University School of Medicine.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Cellular tumor antigen p53 (TP53/p53) 27 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name Contusugene ladenovec Phase 3 [2]
Synonyms
Advexin; Ad5CMV-p53; INGN-004; INGN-201; Ad-p53, Introgen; Gene therapy (p53/adenovirus), University of Texas; Gene therapy (p53/adenoviral), Introgen/Aventis; Gene therapy (p53/adenoviral), Introgen/RPR
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MOA Modulator
External Link
TTD: D04FYL
 Compound Name QPI-1002 Phase 3 [3]
MOA Modulator
External Link
TTD: D0D5ZU
 Compound Name Thymoquinone Phase 2/3 [4]
Synonyms
490-91-5; Thymoquinon; p-Cymene-2,5-dione; 2-Isopropyl-5-methyl-1,4-benzoquinone; 2,5-CYCLOHEXADIENE-1,4-DIONE, 2-METHYL-5-(1-METHYLETHYL)-; 2-Isopropyl-5-methyl-p-benzoquinone; 2-Isopropyl-5-methylbenzoquinone; Polythymoquinone; 5-Isopropyl-2-methyl-1,4-benzoquinone; 2-Isopropyl-5-methylbenzo-1,4-quinone; p-Mentha-3,6-diene-2,5-dione; NSC 2228; 2-Isopropyl-5-methylcyclohexa-2,5-diene-1,4-dione; 2-Methyl-5-isopropyl-p-benzoquinone; 2-methyl-5-propan-2-ylcyclohexa-2,5-diene-1,4-dione; NSC2228; 2-methyl-5-(propan-2-yl)cyclohexa-2,5-diene-1,4-dione; UNII-O60IE26NUF; 2-Methyl-5-isopropyl-1,4-benzoquinone; O60IE26NUF; 2,5-Cyclohexadiene-1,4-dione, 5-isopropyl-2-methyl-; NSC-2228; 5-Isopropyl-2-methyl-p-benzoquinone; MFCD00001602; 2-Methyl-5-(1-methylethyl)-2,5-cyclohexadiene-1,4-dione; p-Mentha-3,6-diene-2,5-dione (8CI); 5-Isopropyl-2-methyl-2,5-Cyclohexadiene-1,4-dione; CCRIS 7152; EINECS 207-721-1; 2-methyl-5-(methylethyl)cyclohexa-2,5-diene-1,4-dione; BRN 1939047; thymolquinone; Thymoil; AI3-17758; 4hco; p-Mentha-3,5-dione; Spectrum_001237; SpecPlus_000457; Thymoquinone, >=98%; Spectrum2_000700; Spectrum3_001345; Spectrum4_001895; Spectrum5_000550; BSPBio_003129; KBioGR_002455; KBioSS_001717; DivK1c_006553; SCHEMBL542535; SPBio_000859; CHEMBL1672002; DTXSID9060079; KBio1_001497; KBio2_001717; KBio2_004285; KBio2_006853; KBio3_002349; Thymoquinone, analytical standard; CHEBI:113532; 2-Methyl-5-iso-propylbenzoquinone; BDBM166686; ZINC164367; BCP16946; HY-D0803; WLN: L6V DVJ B1 EY1&1; 2,4-dione, 5-isopropyl-2-methyl-; ANW-41600; CCG-40027; s4761; SBB008296; AKOS003368628; MCULE-9899033250; NCGC00178250-01; NCGC00178250-05; 73940-92-8; AK101679; AS-11327; 2-Isopropyl-5-methylbenzo-1,4-quinone #; 2,4-dione, 2-methyl-5-(1-methylethyl)-; CS-0012226; FT-0612708; ST45023960; K-9199; SR-05000002192; Q7799650; SR-05000002192-2; W-202869; BRD-K97566842-001-03-5; 2-methyl-5-(propan-2-yl)cyclohexa-2,5-diene-1,4-dione (F8); 2-Methyl-5-(1-methylethyl)-2,5-cyclohexadiene-1,4-dione, 9CI
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MOA Inhibitor
External Link
CID: 10281
TTD: DY4OZ6
 Compound Name SGT-53 Phase 2 [5]
Synonyms
P53 gene stimulator (solid tumor), Synergene Therapeutics
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MOA Stimulator
External Link
TTD: D02EOH
 Compound Name APR-246 Phase 2 [6]
Synonyms
Eprenetapopt
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MOA Stimulator
External Link
CID: 52918385
TTD: D03XTY
DrugBank: DB11684
 Compound Name Ad-p53 Phase 2 [7]
Synonyms
P53 gene therapy, Transgene/Schering-Plough; Ad-p53, Transgene/Schering-Plough
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MOA Modulator
External Link
TTD: D0CO9B
 Compound Name Kevetrin Phase 2 [8]
MOA Stimulator
External Link
CID: 437740
TTD: D0K7DV
DrugBank: DB13010
 Compound Name INGN-225 Phase 2 [9]
Synonyms
Cancer vaccine (p53), Introgen
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External Link
TTD: D0V2SP
 Compound Name ALT-801 Phase 2 [10]
Synonyms
ALT-801 (donor lymphocyte infusion, cancer); ALT-801 (donor lymphocyte infusion, cancer), Altor; STAR IL-2 conjugate (donor lymphocyte infusion, cancer), Altor; STAR-Ck (donor lymphocyte infusion, cancer), Altor; Soluble T-cell Antigen Receptor IL-2 conjugate (donor lymphocyte infusion, cancer), Altor
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MOA Immunomodulator (Immunostimulant)
External Link
TTD: D0V5JH
 Compound Name APG-115 Phase 2 [8]
Synonyms
15Qau0SI9J; UNII-15QAU0SI9J; 1818393-16-6; APG 115 [WHO-DD]; SCHEMBL17189805; Bicyclo(2.2.2)octane-1-carboxylic acid, 4-((((3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-1'',2''-dihydro-2''-oxodispiro(cyclohexane-1,2'-pyrrolidine-3',3''-(3H)indol)-5'-yl)carbonyl)amino)-
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MOA Inhibitor
External Link
CID: 91972012
TTD: D04SXL
 Compound Name ISA-P53-01 Phase 1/2 [11]
Synonyms
P53-SLP; P53 vaccine (colorectal/ovarian cancer), ISA Pharmaceuticals; P53 vaccine (Montanide ISA-51 adjuvanted, colorectal/ovarian cancer), ISA Pharmaceuticals
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External Link
TTD: D0KK4N
 Compound Name SAR-405838 Phase 1 [12]
Synonyms
AT-219; MI-147; MI-219; MI-319; MI-43; MI-5; MI-63; MI-772; MI-773; MI-519-64; P53-HDM2 protein interaction inhibitors (cancer); P53-HDM2 protein interaction inhibitors (cancer), Ascenta/Sanofi; P53-HDM2 protein interaction inhibitors (cancer), Ascenta/sanofi-aventis
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MOA Modulator
External Link
CID: 53476877
TTD: D03YSQ
DrugBank: DB12541
 Compound Name Dendritic cell vaccine Phase 1 [13]
Synonyms
Dendritic cell vaccine (injectable, head and neck cancer); Dendritic cell vaccine (injectable, head and neck cancer), National Cancer Institute; Mutant p53 peptide pulsed dendritic cell vaccine (injectable, head and neck cancer), National Cancer Institute
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External Link
TTD: D05CPS
 Compound Name ONYX-015 Phase 1 [14]
Synonyms
Dl1520; E1B-deleted adenovirus (cancer), ONYX
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MOA Modulator
External Link
TTD: D0G7YS
 Compound Name COTI-2 Phase 1 [8]
Synonyms
UNII-2BTA1O65BR; 2BTA1O65BR; 1039455-84-9; ZINC114475331; CS-8156; HY-19896; 1-Piperazinecarbothioic acid, 4-(2-pyridinyl)-, 2-(6,7-dihydro-8(5H)-quinolinylidene)hydrazide
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MOA Modulator
External Link
CID: 91810660
TTD: D0G8CU
 Compound Name CGM097 Phase 1 [3]
MOA Modulator
External Link
CID: 53240420
TTD: D0Q7AG
 Compound Name HDM201 Phase 1 [15]
MOA Inhibitor
External Link
CID: 71678098
TTD: D01KTG
 Compound Name INGN-234 Discontinued in Phase 2 [16]
Synonyms
P53 tumor suppressor (topical formulation), Introgen
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MOA Suppressor
External Link
TTD: D05AHK
 Compound Name Pifithrin-alpha Terminated [17]
Synonyms
P53 inhibitor, Univ of Illinois; PFT-alpha; PFT-beta; Pifithrin compounds, Quark; Pifithrin-beta
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MOA Inhibitor
External Link
CID: 9929138
TTD: D02NYK
 Compound Name TAR-1 Terminated [18]
Synonyms
P53 protein modulator (single-chain antibody fragment, cancer), Ramot/Champions
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External Link
TTD: D0LG1K
 Compound Name 1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine Investigative [19]
Synonyms
PhiKan 083; [(9-ethyl-9H-carbazol-3-yl)methyl](methyl)amine; EN300-43214; 880813-36-5; AC1NGDXR; PhiKan-083; BAS 13152361; PhiKan-083 Hydrochloride; CHEMBL1235116; SCHEMBL20181195; AC1Q3123; ZINC3888893; STK511393; IMED102848735; AKOS000284549; MCULE-1841863738; DB08363; NCGC00379107-01; NCGC00379107-02; ST072505; [(9-ethylcarbazol-3-yl)methyl]methylamine; HY-108637; CS-0029368; [(9-ethylcarbazol-3-yl)methyl](methyl)amine; 1-(9-ethylcarbazol-3-yl)-N-methylmethanamine
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MOA Inhibitor
External Link
CID: 4722579
TTD: D08PLU
DrugBank: DB08363
 Compound Name NUTLIN-3 Investigative [20]
Synonyms
548472-68-0; 890090-75-2; nutlin-3A; nutlin 3; (+/-)-Nutlin3; CHEMBL211045; Nutlin 3(Random Configuration); MDM2 Antagonist, Nutlin-3, Racemic; 4-(4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; 4-({4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazol-1-yl}carbonyl)piperazin-2-one; 4-[4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one
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MOA Inhibitor
External Link
CID: 216345
TTD: D01QKK
 Compound Name NU-8231 Investigative [21]
Synonyms
SCHEMBL2454464; CHEMBL360944
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MOA Inhibitor
External Link
CID: 11648438
TTD: D0F1SN
 Compound Name OPI-1002 Phase 2 [22]
External Link
TTD: D02CKH
 Compound Name Cenersen Phase 2 [22]
External Link
CID: 56841947
TTD: D0K4VW
 Compound Name AHL Investigative [22]
Synonyms
AHLi-11; SiRNA therapeutics (hearing loss), Quark; P53 gene-silencing siRNA (hearing loss), Quark
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External Link
TTD: D0T8EL
 Compound Name PC14586 Phase 1/2 [22]
External Link
TTD: D53CGK
Lactate dehydrogenase A (LDHA) 1 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name Nedosiran Approved [22]
Synonyms
nedosiran
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External Link
TTD: DZ8DF0
2D0Y: Melanoma of uvea 1 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Hepzato Phase 3 [23]
External Link
TTD: DFB62M
References
Ref 1 Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 2021 Mar 16;22(1):85. doi: 10.1186/s13059-021-02308-z.
Ref 2 A review of contusugene ladenovec (Advexin) p53 therapy. Curr Opin Mol Ther. 2009 Feb;11(1):54-61.
Ref 3 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics. 2005 Aug;86(2):127-41. doi: 10.1016/j.ygeno.2005.04.008.
Ref 4 Apoptosis as a mechanism for the treatment of adult T cell leukemia: promising drugs from benchside to bedside. Drug Discov Today. 2020 Jul;25(7):1189-1197. doi: 10.1016/j.drudis.2020.04.023. Epub 2020 May 7.
Ref 5 Transferrin receptor targeting nanomedicine delivering wild-type p53 gene sensitizes pancreatic cancer to gemcitabine therapy. Cancer Gene Ther. 2013 Apr;20(4):222-8. doi: 10.1038/cgt.2013.9. Epub 2013 Mar 8.
Ref 6 APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 2013 Oct 24;4(10):e881. doi: 10.1038/cddis.2013.417.
Ref 7 Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer. Cancer Gene Ther. 2003 Mar;10(3):224-38. doi: 10.1038/sj.cgt.7700562.
Ref 8 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 9 INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect. Expert Opin Biol Ther. 2010 Jun;10(6):983-91. doi: 10.1517/14712598.2010.484801.
Ref 10 Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies. Clin Cancer Res. 2011 Dec 15;17(24):7765-75. doi: 10.1158/1078-0432.CCR-11-1817. Epub 2011 Oct 12.
Ref 11 WO patent application no. 2013,1850,32, Nanotherapeutics for drug targeting.
Ref 12 SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res. 2014 Oct 15;74(20):5855-65. doi: 10.1158/0008-5472.CAN-14-0799. Epub 2014 Aug 21.
Ref 13 Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study. Cancer Immunol Immunother. 2004 Jul;53(7):633-41. doi: 10.1007/s00262-003-0493-5. Epub 2004 Feb 25.
Ref 14 Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell. 2004 Dec;6(6):611-23. doi: 10.1016/j.ccr.2004.11.012.
Ref 15 National Cancer Institute Drug Dictionary (drug id 761551).
Ref 16 Prevent Oral Cancer With Mouthwash. Introgen Therapeutics.
Ref 17 An evaluation of the ability of pifithrin-alpha and -beta to inhibit p53 function in two wild-type p53 human tumor cell lines. Mol Cancer Ther. 2005 Sep;4(9):1369-77. doi: 10.1158/1535-7163.MCT-04-0341.
Ref 18 Regulation of host gene expression by HIV-1 TAR microRNAs. Retrovirology. 2013; 10: 86.
Ref 19 The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. doi: 10.1093/nar/28.1.235.
Ref 20 Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein interaction. J Med Chem. 2009 Nov 26;52(22):7044-53. doi: 10.1021/jm900681h.
Ref 21 Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold. J Med Chem. 2006 Oct 19;49(21):6209-21. doi: 10.1021/jm0601194.
Ref 22 TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751.
Ref 23 ClinicalTrials.gov (NCT05022901) An Open-Label Expanded Access Study of the Melphalan/Hepatic Delivery System (HDS) in Patients With Hepatic Dominant Ocular Melanoma. U.S.National Institutes of Health.