m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03330
 [1], [2]
Histone modification H3K4me3 KDM5A hsa-miR-495 Indirect Enhancement m6A modification NKX3-1 NKX3-1 YTHDF2 : m6A sites
m6A Modification:
m6A Regulator YTH domain-containing family protein 2 (YTHDF2) READER
 Regulator Info 
m6A Target Homeobox protein Nkx-3.1 (NKX3-1)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Lysine-specific demethylase 5A (KDM5A) ERASER View Details
Regulated Target Histone H3 lysine 4 trimethylation (H3K4me3) View Details
Downstream Gene hsa-miR-495 View Details
Crosstalk Relationship Histone modification  →  m6A Enhancement
Crosstalk Mechanism histone modification indirectly regulates m6A modification through downstream signaling pathways
Crosstalk Summary KDM5A, as a Histone H3 lysine 4 trimethylation (H3K4me3) demethylase, bound to the hsa-miR-495 promoter, which led to inhibition of its transcription and expression. As a target of miR-495, YTHDF2 could inhibit MOB3B expression by recognizing m6A modification of MOB3B mRNA and inducing mRNA degradation. Knock-down of YTHDF2 or METTL3 significantly induced the expression of LHPP and Homeobox protein Nkx-3.1 (NKX3-1) at both mRNA and protein level with inhibited phosphorylated AKT. YTHDF2 mediates the mRNA degradation of the tumor suppressors LHPP and NKX3-1 in m6A-dependent way to regulate AKT phosphorylation-induced tumor progression in prostate cancer.
Responsed Disease Prostate cancer ICD-11: 2C82
 Disease Info 
Pathway Response Oxidative phosphorylation hsa00190
Cell Process Cell proliferation
Cell migration
Cell invasion
Cell apoptosis
In-vitro Model
 RWPE-1 Normal Homo sapiens CVCL_3791
DU145 Prostate carcinoma Homo sapiens CVCL_0105
PC-3 Prostate carcinoma Homo sapiens CVCL_0035
22Rv1 Prostate carcinoma Homo sapiens CVCL_1045
VCaP Prostate carcinoma Homo sapiens CVCL_2235
In-vivo Model Approximately 2 × 106 PCa cells (PC-3 shNC, shYTHDF2, shMETTL3 cell lines) per mouse suspended in 100 uL PBS were injected in the flank of male BALB/c nude mice (4 weeks old). During the 40-day observation, the tumor size (V = (width2× length × 0.52)) was measured with vernier caliper. Approximately 1.5 × 106 PCa cells suspended in 100 uL of PBS (PC-3 shNC, shYTHDF2, and shMETTL3 cell lines) per mouse were injected into the tail vein of male BALB/c nude mice (4 weeks old). The IVIS Spectrum animal imaging system (PerkinElmer) was used to evaluate the tumor growth (40 days) and whole metastasis conditions (4 weeks and 6 weeks) with 100 uL XenoLight D-luciferin Potassium Salt (15 mg/ml, Perkin Elmer) per mouse. Mice were anesthetized and then sacrificed for tumors and metastases which were sent for further organ-localized imaging as above, IHC staining and hematoxylin-eosin (H&E) staining.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Lysine-specific demethylase 5A (KDM5A) 21 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name 6EP Patented [3]
Synonyms
2-{5-[(4-Chloro-2-Methylphenyl)methoxy]-1h-Pyrazol-1-Yl}pyridine-4-Carboxylic Acid; 1613410-75-5; CHEMBL3786952; SCHEMBL15778339; BDBM191600; NCGC00390881-02; QC3611,QC-3611,QC 3611; 2-(5-((4-chloro-2-methylbenzyl)oxy)-1Hpyrazol-1-yl)isonicotinic acid (N19)
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 74766595
TTD: D00SUC
 Compound Name BDBM50158803 Patented [4]
Synonyms
CHEMBL3787438; SCHEMBL15792889
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 90216982
TTD: D01WHH
 Compound Name US10022354, Example 151 Patented [5]
Synonyms
SCHEMBL19513974; CHEMBL4060968; BDBM281211
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 0.065 nM
External Link
CID: 132054530
TTD: D03POM
 Compound Name US9714230, 12 Patented [3]
Synonyms
SCHEMBL15778399; LKBZHRSAENXIOI-UHFFFAOYSA-N; BDBM263942; 2-(5-p-tolyl-1H-pyrazol-1- yl)isonicotinic acid; 2-(5-p-tolyl-1H-pyrazol-1-yl)isonicotinic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 550 nM
External Link
CID: 76901247
TTD: D03TKM
 Compound Name BDBM50158791 Patented [6]
Synonyms
CHEMBL3786596; SCHEMBL15818867; SCHEMBL19646964
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 550 nM
External Link
CID: 77106319
TTD: D05CCY
 Compound Name US10040779, Example 4 Patented [7]
Synonyms
SCHEMBL15792083; BDBM277707; 3-[(5-chloro-1-methyl-1H-indazol-3-yl)amino]pyridine-4-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 0.1nM
External Link
CID: 75202257
TTD: D06TKT
 Compound Name US9611221, Example 9 Patented [8]
Synonyms
3-[(biphenyl-4-ylmethyl)amino]pyridine-4-carboxylic acid; SCHEMBL15286753; RNBCOBWQQCESLL-UHFFFAOYSA-N; BDBM314105
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 71766727
TTD: D09CWB
 Compound Name US9714230, 46 Patented [9]
Synonyms
SCHEMBL15778753; MITOFELVTHNBGA-UHFFFAOYSA-N; BDBM263981; 2-(5-(4-bromophenyl)-1H-pyrazol- 1-yl)isonicotinic acid; 2-[5-(4-bromophenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 10nM
External Link
CID: 86725517
TTD: D0F3TL
 Compound Name BDBM50158794 Patented [7]
Synonyms
CHEMBL3785470; SCHEMBL15792416
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 0.1nM
External Link
CID: 76282772
TTD: D0G8QR
 Compound Name BDBM50158703 Patented [3]
Synonyms
CHEMBL3785832; SCHEMBL15777940
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 90204862
TTD: D0GH8J
 Compound Name AKOS020330656 Patented [10]
Synonyms
CHEMBL3774545; SCHEMBL15820618; RFUZGPWCXINBNW-UHFFFAOYSA-N; BDBM50153334; ZINC123452149; 3-{[(5-methylthiophen-2-yl)methyl]amino}pyridine-4-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 77106317
TTD: D0HT9Q
 Compound Name BDBM50158755 Patented [11]
Synonyms
CHEMBL3786579; SCHEMBL15778210
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 90205053
TTD: D0K4LW
 Compound Name US10174026, Example 99 Patented [12]
Synonyms
SCHEMBL16157351; BDBM320432; 2-(pyrrolidin-1-ylcarbonyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 85469291
TTD: D0N9JZ
 Compound Name AKOS020330481 Patented [8]
Synonyms
3-[(4-methoxybenzyl)amino]pyridine-4-carboxylic acid; SCHEMBL4855920; US9611221, Example 7; XKZFNTZMCLZYHZ-UHFFFAOYSA-N; BDBM314103; 3[(4-methoxybenzyl)amino]pyridine-4-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 550 nM
External Link
CID: 59699608
TTD: D0NG8M
 Compound Name US10022354, Example 5 Patented [5]
Synonyms
SCHEMBL17682496; CHEMBL4062756; BDBM281065
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 7.4 nM
External Link
CID: 121279569
TTD: D0NM3B
 Compound Name NCGC00381656-01 Patented [13]
Synonyms
CHEMBL4100530; SCHEMBL16157407; BDBM320423; US10174026, Example 88; 2-[(2-chlorophenyl)-propoxy- methyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 117637389
TTD: D0PQ5P
 Compound Name US10174026, Example 2 Patented [12]
Synonyms
SCHEMBL16149258; FEZIKLVLFANZBD-UHFFFAOYSA-N; BDBM320362; 2-phenyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid; 2-phenyl-1H-pyrrolo[3,2-b] pyridine-7-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 550 nM
External Link
CID: 86280871
TTD: D0R2GT
 Compound Name US10022354, Example 152 Patented [5]
Synonyms
CHEMBL4059597; SCHEMBL17682668; BDBM281212
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 0.083 nM
External Link
CID: 121279737
TTD: D0T8YT
 Compound Name US10040779, Example 1 Patented [7]
Synonyms
SCHEMBL15792304; BDBM277704; 3-[(1-methyl-1H-indazol-3-yl)amino]pyridine-4-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 0.1nM
External Link
CID: 76282043
TTD: D0VZ5E
 Compound Name 1190312-92-5 Patented [12]
Synonyms
3-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid; 3-CHLORO-4-AZAINDOLE-7-CARBOXYLIC ACID; SCHEMBL16157363; US10174026, Example 1; UAFNSWUBMGTOQA-UHFFFAOYSA-N; BDBM320361; ZINC44713035; 3-chloro-1H-pyrrolo[3,2-b] pyridine-7-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 5500 nM
External Link
CID: 53412620
TTD: D0ZJ0Z
 Compound Name PBIT Investigative [14]
Synonyms
2514-30-9; 2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one; 2-(4-methylphenyl)-1,2-benzothiazol-3-one; MLS000583746; 2-(p-Tolyl)benzo[d]isothiazol-3(2H)-one; 2-(p-tolyl)-1,2-benzothiazol-3-one; SMR000200989; 2-(4-methylphenyl)-1,2-benzothiazol-3(2H)-one; 1,2-Benzisothiazol-3(2H)-one, 2-(4-methylphenyl)-; 2-(4-methylphenyl)-2,3-dihydro-1,2-benzothiazol-3-one; ChemDiv3_007090; AC1LIP69; cid_935415; SCHEMBL2443755; GTPL7026; CHEMBL1336959; CTK0J4356; BDBM34737; AOB6896; DTXSID10359056; MolPort-002-285-696; HMS2576N21
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 935415
TTD: D0IQ7Y
2C82: Prostate cancer 1 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name CC-94676 Phase 1 [15]
External Link
TTD: DNY63Z
References
Ref 1 Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression. J Exp Clin Cancer Res. 2020 Oct 21;39(1):223. doi: 10.1186/s13046-020-01735-3.
Ref 2 YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer. 2020 Oct 29;19(1):152. doi: 10.1186/s12943-020-01267-6.
Ref 3 Histone demethylase inhibitors. US9714230.
Ref 4 Histone demethylase inhibitors. US9617242.
Ref 5 IRE-1 inhibitors
Ref 6 Histone demethylase inhibitors. US9725441.
Ref 7 Histone demethylase inhibitors. US10040779.
Ref 8 Histone demethylase inhibitors. US9611221.
Ref 9 Histone demethylase inhibitors. US9604961.
Ref 10 Histone demethylase inhibitors. US10179769.
Ref 11 Histone demethylase inhibitors. US10173996.
Ref 12 Histone demethylase inhibitors. US10174026.
Ref 13 Histone demethylase inhibitors. US9738637.
Ref 14 Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen. J Biol Chem. 2013 Mar 29;288(13):9408-17. doi: 10.1074/jbc.M112.419861. Epub 2013 Feb 13.
Ref 15 ClinicalTrials.gov (NCT04428788) Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CC-94676 in Subjects With Metastatic Castration-Resistant Prostate Cancer. U.S. National Institutes of Health.