m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03561
 [1], [2]
Histone modification H3K27ac EP300 LINC01605 Indirect Enhancement m6A modification BHLHE41 BHLHE41 METTL3 Methylation : m6A sites
m6A Modification:
m6A Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
m6A Target Class E basic helix-loop-helix protein 41 (BHLHE41)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Histone acetyltransferase p300 (P300) WRITER View Details
Regulated Target Histone H3 lysine 27 acetylation (H3K27ac) View Details
Downstream Gene LINC01605 View Details
Crosstalk Relationship Histone modification  →  m6A Enhancement
Crosstalk Mechanism histone modification indirectly regulates m6A modification through downstream signaling pathways
Crosstalk Summary LINC01605 was regulated by SMYD2-p300-mediated modifications of histone H3K4me3 as well as Histone H3 lysine 27 acetylation (H3K27ac). LINC01605 was found to bind to METTL3 and promote the m6A modification of SPTBN2 mRNA, thereby facilitating the translation of SPTBN2. METTL3 promoted Class E basic helix-loop-helix protein 41 (BHLHE41) expression in m6A-dependent manner, which subsequently induced CXCL1 transcription to enhance MDSC migration in vitro. METTL3 as a potential therapeutic target for CRC immunotherapy whose inhibition reverses immune suppression through m6A-BHLHE41-CXCL1 axis.
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Pathway Response Cytokine-cytokine receptor interaction hsa04060
Chemokine signaling pathway hsa04062
Cell Process Cell immunity
Cell growth
Cell migration
In-vitro Model
 CT26 Mouse colon adenocarcinoma Mus musculus CVCL_7254
MC-38 Mouse colon adenocarcinoma Mus musculus CVCL_B288
HEK293T Normal Homo sapiens CVCL_0063
In-vivo Model METTL3 knockout or control CT26 and MC38 cells were injected subcutaneously into the dorsal flank of each 4- to 6-week-old male immunocompetent BALB/c and C57BL/6 mice, respectively. Anti-Gr-1 (BE0075; Bio-X-Cell, Lebanon, NH) or immunoglobulin (Ig)G isotype control (BE0090, Bio-XCell) was given every other day via intraperitoneal injection (150 ug/mouse). SB-265610 (Tocris, Bristol, UK) or phosphate-buffered saline was administrated through intraperitoneal injections at a dosage of 2 mg/kg per day. Tumor sizes were measured every other day. To establish an orthotopic mouse model of CRC, 5- to 6-week-old male C57BL/6 mice were treated with 1.7% dextran sodium sulfate in drinking water for 5 days, and then allowed to recover for 3 days. After 24 hours of fasting, METTL3 knockout or control MC38 cells suspended in 50 ul of 1 mg/mL Matrigel-phosphate-buffered saline (Corning, Corning, NY) were instilled into the colon lumen of anesthetized mice, coated sparingly with Vaseline.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Histone acetyltransferase p300 (P300) 2 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name CCS1477 Phase 1/2 [3]
Synonyms
CCS-1477; CBP-IN-1; 2222941-37-7; (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one; SCHEMBL20094038; SCHEMBL21515367; SCHEMBL22134021; EX-A3687; NSC818619; NSC-818619; HY-111784; CS-0091862; (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one
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MOA Inhibitor
External Link
CID: 134457551
TTD: DIY4C2
 Compound Name FT-7051 Phase 1 [4]
MOA Inhibitor
External Link
TTD: DT8IL6
2B91: Colorectal cancer 25 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Retifanlimab Approved [5]
Synonyms
INCMGA0012; Retifanlimab
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External Link
TTD: D0PG5O
 Compound Name Aflibercept Approved [6]
Synonyms
Ziv-Aflibercept; Zaltrap (TN); VEGF Trap; VEGF Trap-Eye
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External Link
TTD: D0C9ET
 Compound Name Regorafenib Approved [7]
Synonyms
755037-03-7; BAY 73-4506; Regorafenibum; Stivarga; 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide; BAY73-4506; Regorafenib (BAY 73-4506); UNII-24T2A1DOYB; 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide; BAY-73-4506; 24T2A1DOYB; CHEMBL1946170; CHEBI:68647; Stivarga (TN); BAY73-4506 hydrochloride; Regorafenib [USAN:INN]
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External Link
CID: 11167602
TTD: D09GDD
DrugBank: DB08896
 Compound Name Bevacizumab Approved [8]
Synonyms
Bevacizumab (ophthalmic slow-release tissue tablet)
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External Link
TTD: D04KBL
 Compound Name SYM-004 Phase 3 [8]
Synonyms
Chimeric IgG1 antibody 1024 (cancer), Symphogen; Chimeric IgG1 antibody 992 (cancer), Symphogen; Chimeric IgG1 antibodies992 + 1024 (cancer), Symphogen
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External Link
TTD: D0CR8H
 Compound Name Bevacizumab + Erlotinib Phase 3 [9]
External Link
TTD: D09BKY
 Compound Name CPI-613 Phase 3 [8]
Synonyms
95809-78-2; 6,8-bis(benzylthio)octanoic acid; CPI 613; MLS006010202; SCHEMBL1062218; 6,8-Bis(benzylsulfanyl)octanoic acid; Octanoic acid, 6,8-bis((phenylmethyl)thio)-; Octanoic acid, 6,8-bis[(phenylMethyl)thio]-; 6,8-Bis[(phenylmethyl)thio]octanoic acid; CPI613; CHEMBL3186849; QCR-193; AOB1058; MolPort-023-219-128; HMS3656L06; C22H28O2S2; BCP04663; EX-A2043; s2776; AKOS025142095; BCP9000552; DB12109; RL06062; CS-0961; NCGC00344764-01; SMR004701300; AS-16613; BC261916; AK174899; HY-15453; BCP0726000030; KB-293127; AB0035874
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External Link
CID: 24770514
TTD: D07NVI
DrugBank: DB12109
 Compound Name Bevacizumab Approved [6]
External Link
TTD: D0FX3U
 Compound Name AlloStim Phase 2/3 [10]
Synonyms
AlloStim (TN)
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External Link
TTD: D0B3CC
 Compound Name Sibrotuzumab Phase 2 [11]
External Link
TTD: DVX3H0
 Compound Name CV301 Phase 2 [12]
External Link
TTD: D9LT5G
 Compound Name Efatutazone Phase 2 [13]
Synonyms
Inolitazone; 223132-37-4; 5-[[4-[[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-yl]methoxy]phenyl]methyl]-2,4-Thiazolidinedione; Efatutazone [INN]; RS5444; CS-7017; SCHEMBL3246054; CHEMBL3545280; JCYNMRJCUYVDBC-UHFFFAOYSA-N; Efatutazone;CS-7017;RS5444; BCP07478; AKOS030526729; DB11894; CS-0778; KB-77905; DA-07988; HY-14792; QC-10456; 4CA-1384; FT-0737589; 5-[4-[6-(4-amino-3 ,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione
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External Link
CID: 9832447
TTD: D0Y8NZ
DrugBank: DB11894
 Compound Name LOR-2040 Phase 2 [14]
External Link
TTD: D0I7NG
 Compound Name RG7221 Phase 2 [15]
External Link
TTD: D06FTM
 Compound Name PEG-SN38 Phase 2 [16]
Synonyms
EZN-2208
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External Link
CID: 59443782
TTD: D05UFP
 Compound Name MEGF0444A Phase 2 [17]
External Link
TTD: D01LES
 Compound Name Encapsulated cell therapy Phase 1/2 [18]
External Link
TTD: D0XY8C
 Compound Name AB928 Phase 1/2 [19]
External Link
CID: 135242184
TTD: D04UBI
 Compound Name MGD007 Phase 1 [15]
External Link
TTD: D00PEN
 Compound Name BNC-101 Phase 1 [20]
External Link
TTD: DD6AZ5
 Compound Name Navicixizumab Phase 1 [8]
External Link
TTD: D00IVN
 Compound Name RG7160 Discontinued in Phase 2 [21]
External Link
TTD: D0E2CQ
 Compound Name Nimesulide Terminated [22]
Synonyms
51803-78-2; N-(4-Nitro-2-phenoxyphenyl)methanesulfonamide; Mesulid; Flogovital; Sulidene; Nimed; R-805; 4-NITRO-2-PHENOXYMETHANESULFONANILIDE; Nisulid; Nimesulidum [INN-Latin]; Nimesulida [INN-Spanish]; R 805; UNII-V4TKW1454M; 4-Nitro-2-phenoxy-methanesulfonanilide; 4'-Nitro-2'-phenoxymethanesulfonanilide; Methanesulfonamide, N-(4-nitro-2-phenoxyphenyl)-; EINECS 257-431-4; 4'-Nitro-2'-phenoxymethansulfonanilid; BRN 2421175; CHEMBL56367; MLS000069680; V4TKW1454M; Methanesulfonanilide, 4'-nitro-2'-phenoxy-; CHEBI:44445; Dulanermin
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External Link
CID: 4495
TTD: D0C0JT
DrugBank: DB04743
 Compound Name Saracatinib Phase 2 [23]
External Link
CID: 10302451
TTD: D05YTN
DrugBank: DB11805
 Compound Name G3139 + Irinotecan Investigative [24]
External Link
CID: 91865905
TTD: D05IAN
References
Ref 1 LINC01605, regulated by the EP300-SMYD2 complex, potentiates the binding between METTL3 and SPTBN2 in colorectal cancer. Cancer Cell Int. 2021 Sep 20;21(1):504. doi: 10.1186/s12935-021-02180-8.
Ref 2 METTL3 Inhibits Antitumor Immunity by Targeting m(6)A-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer. Gastroenterology. 2022 Jun 11:S0016-5085(22)00629-1. doi: 10.1053/j.gastro.2022.06.024. Online ahead of print.
Ref 3 Targeting the p300/CBP Axis in Lethal Prostate Cancer. Cancer Discov. 2021 May;11(5):1118-1137. doi: 10.1158/2159-8290.CD-20-0751. Epub 2021 Jan 11.
Ref 4 Clinical pipeline report, company report or official report of FORMA Therapeutics.
Ref 5 Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signaling Pathway.J Med Chem. 2019 Feb 28;62(4):1715-1730.
Ref 6 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 7 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5891).
Ref 8 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 9 ClinicalTrials.gov (NCT00130728) A Study to Evaluate the Efficacy of Bevacizumab in Combination With Tarceva for Advanced Non-Small Cell Lung Cancer
Ref 10 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 11 ClinicalTrials.gov (NCT02198274) Intravenous BIBH 1 in Patients With Metastatic Colorectal Cancer. U.S. National Institutes of Health.
Ref 12 ClinicalTrials.gov (NCT03547999) A Trial of Perioperative CV301 Vaccination in Combination With Nivolumab and Systemic Chemotherapy for Metastatic CRC. U.S. National Institutes of Health.
Ref 13 ClinicalTrials.gov (NCT02152137) Efatutazone With Paclitaxel Versus Paclitaxel Alone in Treating Patients With Advanced Anaplastic Thyroid Cancer. U.S. National Institutes of Health.
Ref 14 ClinicalTrials.gov (NCT00087165) GTI-2040, Docetaxel, and Prednisone in Treating Patients With Prostate Cancer. U.S. National Institutes of Health.
Ref 15 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 16 ClinicalTrials.gov (NCT01036113) A Phase 2 Study of EZN-2208 in Patients With Metastatic Breast Cancer. U.S. National Institutes of Health.
Ref 17 ClinicalTrials.gov (NCT00909740) A Study of the Safety and Pharmacokinetics of MEGF0444A Administered to Patients With Advanced Solid Tumors. U.S. National Institutes of Health.
Ref 18 VC-01's Path to the Clinic. Viacyte. 2015.
Ref 19 ClinicalTrials.gov (NCT04660812) An Open Label Study Evaluating the Efficacy and Safety of AB928 Based Treatment Combinations in Patients With Metastatic Colorectal Cancer.. U.S. National Institutes of Health.
Ref 20 ClinicalTrials.gov (NCT02726334) A Phase I, Dose Escalation Study of BNC101 in Patients With Metastatic Colorectal Cancer.. U.S. National Institutes of Health.
Ref 21 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029052)
Ref 22 Clinical pipeline report, company report or official report of Genentech (2011).
Ref 23 Phase II Study of Saracatinib (AZD0530) in Patients With Previously Treated Metastatic Colorectal Cancer. Invest New Drugs. 2015 Aug;33(4):977-84.
Ref 24 Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.