m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT02260
 [1], [2]
DNA methylation DNMT1 METTL14 Direct Inhibition m6A modification SLC7A11 SLC7A11 METTL14 Methylation : m6A sites
m6A Modification:
m6A Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
m6A Target Cystine/glutamate transporter (SLC7A11)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type DNA methylation (DNAMeth)
Epigenetic Regulator DNA (cytosine-5)-methyltransferase 1 (DNMT1) WRITER View Details
Regulated Target Methyltransferase-like protein 14 (METTL14) View Details
Crosstalk Relationship DNA methylation  →  m6A Inhibition
Crosstalk Mechanism DNA methylation directly impacts m6A modification through modulating the expression level of m6A regulator
Crosstalk Summary lncRNA UCA1 recruited DNA methyltransferase (DNMT1, DNMT3A, and DNMT3B) to the METTL14 promoter region to inhibit METTL14 expression in breast cancer. m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3beta and activates beta-catenin/TCF4-Cystine/glutamate transporter (SLC7A11)/FPN1 signaling to drive anti-HER2 resistance. Knockdown of METTL14 significantly increased the expression level of FGFR4 in HER2-positive breast cancer cells. FGFR4 reduced the sensitivity of HER2-positive breast cancer to trastuzumab plus pertuzumab or tucatinib. These results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Responsed Drug Pertuzumab
 Drug Info 
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model
 MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
SUM159PT Breast pleomorphic carcinoma Homo sapiens CVCL_5423
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
In-vivo Model Luciferase-labeled rSKBR3 and MDA-MB-361 cells (1 × 107 cells) mixed with 1:1 Matrigel (Corning, 356237) were subcutaneously injected into the fat pads of mice. After a tumor was palpable, the mice were randomized into four groups (five mice per group), and they were treated with vehicle, trastuzumab (20 mg/kg, intraperitoneal administration), roblitinib (30 mg/kg, oral administration), or a combination of both drugs.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Cystine/glutamate transporter (SLC7A11) 1 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name SXC-2023 Phase 2 [3]
MOA Activator
External Link
TTD: D1KO3P
DNA (cytosine-5)-methyltransferase 1 (DNMT1) 27 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name SGI110 Phase 3 [4]
MOA Modulator
External Link
CID: 137295284
TTD: D0Q5KZ
 Compound Name Guadecitabine Phase 3 [5]
Synonyms
UNII-2KT4YN1DP7; 929901-49-5; 2KT4YN1DP7; SGI-110 free acid; Guadecitabine [USAN:INN]; GuadecitabineSGI-110; Guadecitabine (USAN/INN); CHEMBL3544916; Guanosine, 2'-deoxy-5-azacytidylyl-(3'-5')-2'-deoxy-; ZINC43203165; AKOS027321496; AKOS030238181; DB11918; CS-3089; HY-13542; D10877; 2'-deoxy-5-azacytidylyl-(3'-5')-2'-deoxyguanosine
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 135564655
TTD: D0VZ4N
DrugBank: DB11918
 Compound Name CC-486 Phase 3 [6]
Synonyms
AG-14361; AG14361; 328543-09-5; UNII-48N0U0K50I; AG 14361; CHEMBL65892; 48N0U0K50I; Imidazo[4,5,1-jk][1,4]benzodiazepin-7(4H)-one, 2-[4-[(dimethylamino)methyl]phenyl]-5,6-dihydro-; AG-014361; 1-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one; Imidazo(4,5,1-jk)(1,4)benzodiazepin-7(4H)-one, 2-(4-((dimethylamino)methyl)phenyl)-5,6-dihydro-; 2-[4-[(Dimethylamino)methyl]phenyl]-5,6-dihydroimidazo[4,5,1-jk][1,4]benzodiazepin-7(4H)-one; SMR000486393; MLS006011157; MLS001065917; Nucleoside analogue
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 9840076
TTD: D09NTC
 Compound Name S-110 Phase 3 [7]
Synonyms
DNA demethylating agent (myelodysplastic syndrome), Supergen
    Click to Show/Hide
MOA Inhibitor
External Link
TTD: D0A2BO
 Compound Name Palifosfamide Phase 2 [8]
Synonyms
ZIO-201
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 100427
TTD: D04FDN
DrugBank: DB05668
 Compound Name RX-3117 Phase 2 [9]
Synonyms
Antimetabolite (cancer), Rexahn; Antimetabolite (cancer), Rexahn/ Teva
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 11242315
TTD: D0L7WS
 Compound Name Antroquinonol Phase 2 [10]
Synonyms
Hocena; Fungal extract (cancer), Golden Biotechnology
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 24875259
TTD: D0T3AW
DrugBank: DB12326
 Compound Name GSK4172239 Phase 1 [11]
MOA Inhibitor
External Link
TTD: D5QR2M
 Compound Name PMID27376512-Compound-miR-155-5p Patented [12]
MOA Inhibitor
Activity Ki = 27.88 nM
External Link
TTD: D01CGQ
 Compound Name PMID27376512-Compound-Table1Example11 Patented [12]
MOA Inhibitor
Activity IC50 = 39440 nM
External Link
CID: 75201485
TTD: D04JIH
 Compound Name PMID27376512-Compound-Table1Example16 Patented [12]
MOA Inhibitor
Activity IC50 = 22520 nM
External Link
CID: 75201537
TTD: D05DSL
 Compound Name PMID27376512-Compound-Table1Example5 Patented [12]
MOA Inhibitor
Activity IC50(DNMT1) = 3530 nM
External Link
CID: 73774653
TTD: D09FMS
 Compound Name PMID27376512-Compound-asCEBP-2HPE Patented [12]
MOA Inhibitor
Activity Ki = 135.2 nM
External Link
TTD: D0E7OA
 Compound Name PMID27376512-Compound-asCEBP-1 Patented [12]
MOA Inhibitor
Activity Ki = 2003 nM
External Link
TTD: D0G6ON
 Compound Name PMID27376512-Compound-Table1Example4 Patented [12]
MOA Inhibitor
Activity IC50 = 13810 nM
External Link
CID: 75201432
TTD: D0K4YF
 Compound Name PMID27376512-Compound-asCEBP-2 Patented [12]
MOA Inhibitor
Activity Ki = 434.1 nM
External Link
TTD: D0KE4E
 Compound Name PMID27376512-Compound-asCEBP-1HPE Patented [12]
MOA Inhibitor
Activity Ki = 917.5 nM
External Link
TTD: D0LK4R
 Compound Name PMID27376512-Compound-Table1Example8 Patented [12]
MOA Inhibitor
Activity IC50 = 6850 nM
External Link
CID: 75201482
TTD: D0RT6C
 Compound Name PMID27376512-Compound-MTC-433 Patented [12]
MOA Inhibitor
Activity IC50 = 4.22 nM
External Link
TTD: D0U5CK
 Compound Name PMID27376512-Compound-Table1Example30 Patented [12]
MOA Inhibitor
External Link
CID: 75201638
TTD: D0YK6K
 Compound Name PMID27376512-Compound-MTC-424 Patented [12]
MOA Inhibitor
Activity IC50 = 1940 nM
External Link
TTD: D02WRM
 Compound Name PMID27376512-Compound-MTC-427 Patented [12]
MOA Inhibitor
Activity IC50 = 295 nM
External Link
TTD: D0HA0J
 Compound Name PMID27376512-Compound-MTC-422 Patented [12]
MOA Inhibitor
Activity IC50 = 1430 nM
External Link
TTD: D0QY0N
 Compound Name PMID27376512-Compound-MTC-423 Patented [12]
MOA Inhibitor
Activity IC50 = 363 nM
External Link
TTD: D0W9VZ
 Compound Name PMX-700 Investigative [13]
Synonyms
SJ-005019; SJ-005059; DC-010-116; Temozolomide analogs (cancer), Pharminox
    Click to Show/Hide
MOA Modulator
External Link
TTD: D03DTQ
 Compound Name XB-05 Investigative [13]
MOA Inhibitor
External Link
TTD: D0JV8Q
 Compound Name CP-4200 Investigative [13]
Synonyms
Lipidated azacitidine (cancer, Lipid Vector), Clavis Pharma; 5-azacytidine-5'-elaidate
    Click to Show/Hide
MOA Inhibitor
External Link
TTD: D0OT1S
2C60: Breast cancer 2 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Entrectinib Approved [14]
Synonyms
1108743-60-7; RXDX-101; UNII-L5ORF0AN1I; Entrectinib (RXDX-101); L5ORF0AN1I; Benzamide, N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-[(tetrahydro-2H-pyran-4-yl)amino]-; Benzamide, N-(5-((3,5-difluorophenyl)methyl)-1H-indazol-3-yl)-4-(4-methyl-1-piperazinyl)-2-((tetrahydro-2H-pyran-4-yl)amino)-; Entrectinib [USAN:INN]; YMX; Kinome_2659; Entrectinib(rxdx-101); Entrectinib (USAN/INN); SCHEMBL3512601; GTPL8290; CHEMBL1983268; KS-00000TSK
    Click to Show/Hide
External Link
CID: 25141092
TTD: D0O0LS
DrugBank: DB11986
 Compound Name Everolimus Approved [15]
External Link
CID: 6442177
TTD: D09ZSC
DrugBank: DB01590
References
Ref 1 LncRNA UCA1 promotes SOX12 expression in breast cancer by regulating m(6)A modification of miR-375 by METTL14 through DNA methylation. Cancer Gene Ther. 2022 Jul;29(7):1043-1055. doi: 10.1038/s41417-021-00390-w. Epub 2022 Jan 13.
Ref 2 N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nat Commun. 2022 May 13;13(1):2672. doi: 10.1038/s41467-022-30217-7.
Ref 3 Clinical pipeline report, company report or official report of Promentis Pharmaceuticals.
Ref 4 Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. Epigenetics. 2015;10(3):237-46.
Ref 5 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 6 Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia. 2016 Apr;30(4):889-96.
Ref 7 S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther. 2010 May;9(5):1443-50.
Ref 8 Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin. Anticancer Drugs. 2012 Feb;23(2):173-84.
Ref 9 Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). Invest New Drugs. 2013 Dec;31(6):1444-57.
Ref 10 Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential. J Agric Food Chem. 2014 Jun 18;62(24):5625-35.
Ref 11 Clinical pipeline report, company report or official report of GlaxoSmithKline
Ref 12 DNA methyltransferase inhibitors: an updated patent review (2012-2015). Expert Opin Ther Pat. 2016 Sep;26(9):1017-30. doi: 10.1080/13543776.2016.1209488. Epub 2016 Jul 18.
Ref 13 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. (Target id: 2605).
Ref 14 Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372... Cancer Discov. 2017 Apr;7(4):400-409.
Ref 15 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015