m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03370
 [1], [2]
Histone modification PLK3 SETDB1 ALKBH5 Indirect Enhancement m6A modification FOXO1 FOXO1 ALKBH5 Demethylation : m6A sites
m6A Modification:
m6A Regulator RNA demethylase ALKBH5 (ALKBH5) ERASER
 Regulator Info 
m6A Target Forkhead box protein O1 (FOXO1)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Histone-lysine N-methyltransferase SETDB1 (SETDB1) WRITER View Details
Regulated Target Polo like kinase 3 (PLK3) View Details
Downstream Gene ALKBH5 View Details
Crosstalk Relationship Histone modification  →  m6A Enhancement
Crosstalk Mechanism histone modification indirectly regulates m6A modification through downstream signaling pathways
Crosstalk Summary Polo like kinase 3 (PLK3) methylation decreases PLK3 phosphorylation of HIF1alpha and thereby increases HIF1alpha stability. HIF1alpha, in turn, upregulates ALKBH5 to reduce m6A modification of LINC00115, resulting in attenuated degradation of YTHDF2-dependent m6A-modified RNA and enhanced LINC00115 stability. Thus, this positive feedback loop provokes BCSC phenotypes and enhances chemoresistance and metastasis in triple-negative breast cancer. SETDB1 inhibitor TTD-IN with LINC00115 ASO sensitizes PTX-resistant cell response to chemotherapy in a xenograft animal model. Correlative expression of LINC00115, methylation PLK3, SETDB1, and HIF1alpha are prognostic for clinical triple-negative breast cancers.In conclusion, we demonstrated a critical function of ALKBH5-mediated m6A demethylation of Forkhead box protein O1 (FOXO1) mRNA in restoring redox balance, which in turn promoting CSCs characteristics and DOX resistance in TNBC, and suggested that targeting the ALKBH5/FOXO1 axis has therapeutic potential for patients with TNBC refractory to chemotherapy.
Responsed Disease Triple-negative breast cancer ICD-11: 2C6Z
 Disease Info 
Responsed Drug Doxil
 Drug Info 
In-vitro Model
 BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
In-vivo Model 6-week old immunodeficient mice (Guangdong Medical Laboratory Animal Center, Guangzhou, China) were selected for generating a subcutaneous xenograft model. MDA-MB-231/DOX cells were implanted subcutaneously into the immunodeficient mice. 7 days later, mice were randomly divided into 4 groups, administrated with vehicle control, FOXO1 inhibitor AS1842856 (20 mg/kg/day, i. p.), Doxorubicin (5 mg/kg/day, i. p.), and AS1842856 combined with Doxorubicin, respectively. Tumor formation was examined every 4 days.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Forkhead box protein O1 (FOXO1) 10 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name ISIS 188780 Investigative [3]
External Link
TTD: D02DUM
 Compound Name ISIS 188763 Investigative [3]
External Link
TTD: D09NLT
 Compound Name ISIS 188761 Investigative [3]
External Link
TTD: D09XIQ
 Compound Name ISIS 188778 Investigative [3]
External Link
TTD: D0D6YO
 Compound Name ISIS 188782 Investigative [3]
External Link
TTD: D0L0JX
 Compound Name ISIS 188781 Investigative [3]
External Link
TTD: D0L0WC
 Compound Name ISIS 188759 Investigative [3]
External Link
TTD: D0N1RP
 Compound Name ISIS 188757 Investigative [3]
External Link
TTD: D0O3QM
 Compound Name ISIS 188755 Investigative [3]
External Link
TTD: D0U0OE
 Compound Name AS-1708727 Investigative [4]
External Link
TTD: D0W9KE
References
Ref 1 LINC00115 promotes chemoresistant breast cancer stem-like cell stemness and metastasis through SETDB1/PLK3/HIF1alpha signaling. Mol Cancer. 2024 Mar 22;23(1):60. doi: 10.1186/s12943-024-01975-3.
Ref 2 M(6)A demethylase ALKBH5 regulates FOXO1 mRNA stability and chemoresistance in triple-negative breast cancer. Redox Biol. 2024 Feb;69:102993. doi: 10.1016/j.redox.2023.102993. Epub 2023 Dec 12.
Ref 3 US patent application no. 7,229,976, Modulation of forkhead box O1A expression.
Ref 4 TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751.