Molecule Information

General Information of the Molecule (ID: Mol00062)

• Name: Hypoxia-inducible factor 2-alpha (EPAS1) ,Homo sapiens
• Synonyms: EPAS-1; Basic-helix-loop-helix-PAS protein MOP2; Class E basic helix-loop-helix protein 73; bHLHe73; HIF-1-alpha-like factor; HLF; Hypoxia-inducible factor 2-alpha; HIF-2-alpha; HIF2-alpha; Member of PAS protein 2; PAS domain-containing protein 2; BHLHE73; HIF2A; MOP2; PASD2
• Molecule Type: Protein
• Gene Name: EPAS1
• Gene ID: 2034
• Location: chr2:46293667-46386697[+]
• Sequence:
  MTADKEKKRSSSERRKEKSRDAARCRRSKETEVFYELAHELPLPHSVSSHLDKASIMRLA
  ISFLRTHKLLSSVCSENESEAEADQQMDNLYLKALEGFIAVVTQDGDMIFLSENISKFMG
  LTQVELTGHSIFDFTHPCDHEEIRENLSLKNGSGFGKKSKDMSTERDFFMRMKCTVTNRG
  RTVNLKSATWKVLHCTGQVKVYNNCPPHNSLCGYKEPLLSCLIIMCEPIQHPSHMDIPLD
  SKTFLSRHSMDMKFTYCDDRITELIGYHPEELLGRSAYEFYHALDSENMTKSHQNLCTKG
  QVVSGQYRMLAKHGGYVWLETQGTVIYNPRNLQPQCIMCVNYVLSEIEKNDVVFSMDQTE
  SLFKPHLMAMNSIFDSSGKGAVSEKSNFLFTKLKEEPEELAQLAPTPGDAIISLDFGNQN
  FEESSAYGKAILPPSQPWATELRSHSTQSEAGSLPAFTVPQAAAPGSTTPSATSSSSSCS
  TPNSPEDYYTSLDNDLKIEVIEKLFAMDTEAKDQCSTQTDFNELDLETLAPYIPMDGEDF
  QLSPICPEERLLAENPQSTPQHCFSAMTNIFQPLAPVAPHSPFLLDKFQQQLESKKTEPE
  HRPMSSIFFDAGSKASLPPCCGQASTPLSSMGGRSNTQWPPDPPLHFGPTKWAVGDQRTE
  FLGAAPLGPPVSPPHVSTFKTRSAKGFGARGPDVLSPAMVALSNKLKLKRQLEYEEQAFQ
  DLSGGDPPGGSTSHLMWKRMKNLRGGSCPLMPDKPLSANVPNDKFTQNPMRGLGHPLRHL
  PLPQPPSAISPGENSKSRFPPQCYATQYQDYSLSSAHKVSGMASRLLGPSFESYLLPELT
  RYDCEVNVPVLGSSTLLQGGDLLRALDQAT
• Function: Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX1 seems to activate CTAD (By similarity).
• Uniprot ID: EPAS1_HUMAN
• Ensembl ID: ENSG00000116016
• HGNC ID: HGNC:3374

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Dasatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [1]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Dasatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lin-CD34+CD38- cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR660-5p observed in CML LSCs led to the down-regulation of its target EPAS1 and conferred TkI-resistance to CML LSCs in vitro.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastric cancer [2]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Over-expression of EPAS-1 increased the expression of PXR responsive genes, enhanced the proliferation of BGC-823 cells and boosted the resistance of BGC-823 cells against the cytotoxicity of chemotherapeutic drugs, e.g. Mitomycin C and Paclitaxel.EPAS-1 reduces BGC-823 cell apoptosis induced by Mitomycin C and Paclitaxel.

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [1]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lin-CD34+CD38- cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR660-5p observed in CML LSCs led to the down-regulation of its target EPAS1 and conferred TkI-resistance to CML LSCs in vitro.

Mitomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastric cancer [2]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Resistant Drug: Mitomycin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Over-expression of EPAS-1 increased the expression of PXR responsive genes, enhanced the proliferation of BGC-823 cells and boosted the resistance of BGC-823 cells against the cytotoxicity of chemotherapeutic drugs, e.g. Mitomycin C and Paclitaxel.EPAS-1 reduces BGC-823 cell apoptosis induced by Mitomycin C and Paclitaxel.

Ponatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Chronic myeloid leukemia [1]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Resistant Drug: Ponatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Lin-CD34+CD38- cells; Bone; Homo sapiens (Human); N.A.
• In Vitro Model: Lin-CD34-CD38- CML cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The up-regulation of miR660-5p observed in CML LSCs led to the down-regulation of its target EPAS1 and conferred TkI-resistance to CML LSCs in vitro.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Chronic myeloid leukemia [ICD-11: 2A20]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Whole blood
• The Specified Disease: Myelofibrosis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.35E-01; Fold-change: 7.49E-02; Z-score: 5.21E-01
• The Studied Tissue: Whole blood
• The Specified Disease: Polycythemia vera
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.09E-03; Fold-change: 6.29E-02; Z-score: 4.99E-01

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.92E-01; Fold-change: -3.22E-01; Z-score: -4.50E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.03E-03; Fold-change: 3.67E-01; Z-score: 6.93E-01

References

• Ref 1: Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells. Oncotarget. 2017 Jul 25;8(30):49451-49469. doi: 10.18632/oncotarget.17706.
• Ref 2: Cross-talk between EPAS-1/HIF-2Alpha and PXR signaling pathway regulates multi-drug resistance of stomach cancer cell .Int J Biochem Cell Biol. 2016 Mar;72:73-88. doi: 10.1016/j.biocel.2016.01.006. Epub 2016 Jan 16. 10.1016/j.biocel.2016.01.006