Molecule Information

General Information of the Molecule (ID: Mol04413)

• Name: Hypoxia-inducible factor 1-alpha (HIF1A) ,Homo sapiens
• Synonyms: ARNT-interacting protein; Basic-helix-loop-helix-PAS protein MOP1 ; Class E basic helix-loop-helix protein 78; Member of PAS protein 1 ; PAS domain-containing protein 8
• Molecule Type: Protein
• Gene Name: HIF1A
• Gene ID: 3091
• Sequence:
  MEGAGGANDKKKISSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVM
  RLTISYLRVRKLLDAGDLDIEDDMKAQMNCFYLKALDGFVMVLTDDGDMIYISDNVNKY
  M GLTQFELTGHSVFDFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTSR
  GR TMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLICEPIPHPSNIEIPL
  DSK TFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFT
  KGQV TTGQYRMLAKRGGYVWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQ
  QTECV LKPVESSDMKMTQLFTKVESEDTSSLFDKLKKEPDALTLLAPAAGDTIISLDFG
  SNDTET DDQQLEEVPLYNDVMLPSPNEKLQNINLAMSPLPTAETPKPLRSSADPALNQE
  VALKLEP NPESLELSFTMPQIQDQTPSPSDGSTRQSSPEPNSPSEYCFYVDSDMVNEFK
  LELVEKLF AEDTEAKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESSSASPE
  SASPQSTVT VFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILIASPSPTHIHKE
  TTSATSSPYR DTQSRTASPNRAGKGVIEQTEKSHPRSPNVLSVALSQRTTVPEEELNPK
  ILALQNAQRKR KMEHDGSLFQAVGIGTLLQQPDDHAATTSLSWKRVKGCKSSEQNGMEQ
  KTIILIPSDLAC RLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN
• Function: Functions as a master transcriptional regulator of theadaptive response to hypoxia .Under hypoxic conditions, activates the transcription of over 40 genes,including erythropoietin, glucose transporters, glycolytic enzymes,vascular endothelial growth factor, HILPDA, and other genes whoseprotein products increase oxygen delivery or facilitate metabolicadaptation to hypoxia . Plays an essentialrole in embryonic vascularization, tumor angiogenesis andpathophysiology of ischemic disease . Heterodimerizeswith ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' withinthe hypoxia response element of target gene promoters . Activation requires recruitment of transcriptionalcoactivators such as CREBBP and EP300 . Activity is enhanced by interaction with NCOA1 and/orNCOA2 . Interaction with redox regulatory proteinAPEX1 seems to activate CTAD and potentiates activation by NCOA1 andCREBBP . Involved in the axonaldistribution and transport of mitochondria in neurons during hypoxia. {ECO:0000250|UniProtKB:Q61221,ECO:0000269|PubMed:10202154, ECO:0000269|PubMed:10594042,ECO:0000269|PubMed:11292861, ECO:0000269|PubMed:11566883,ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16543236,ECO:0000269|PubMed:16973622, ECO:0000269|PubMed:17610843,ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:19528298,ECO:0000269|PubMed:20624928, ECO:0000269|PubMed:22009797,ECO:0000269|PubMed:30125331, ECO:0000269|PubMed:9887100}.; Upon infection by human coronavirusSARS-CoV-2, is required for induction of glycolysis in monocytes andthe consequent pro-inflammatory state . In monocytes,induces expression of ACE2 and cytokines such as IL1B, TNF, IL6, andinterferons . Promotes human coronavirus SARS-CoV-2replication and monocyte inflammatory response .{ECO:0000269|PubMed:32697943}.
• Uniprot ID: HIF1A_HUMAN
• Ensembl ID: ENSG0000010064417
• HGNC ID: HGNC:4910

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) 2 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Bladder cancer [ICD-11: 2C94.0] [1]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF1alpha stabilization signaling pathway; Regulation; N.A.
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vivo Model: BALB/c female nude mice model; Mus musculus
• Experiment for Molecule Alteration: MS analysis; Western blot assay; Immunohistochemistry
• Experiment for Drug Resistance: IC50 assay; Cell proliferation assay; Migration ability assay; Invasion ability assay; Apoptosis assay
• Mechanism Description: Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in?vitro and in?vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed.

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Bladder cancer [ICD-11: 2C94.0] [1]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Aerobic glycolysis signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: FGFR/AKT/ERK signaling pathway; Regulation; N.A.
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vivo Model: BALB/c female nude mice model; Mus musculus
• Experiment for Molecule Alteration: MS analysis; Western blot assay; Immunohistochemistry
• Experiment for Drug Resistance: IC50 assay; Cell proliferation assay; Migration ability assay; Invasion ability assay; Apoptosis assay
• Mechanism Description: Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1alpha expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion.

Disease Class: Bladder cancer [ICD-11: 2C94.0] [1]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Aerobic glycolysis signaling pathway; Regulation; N.A.
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Trypan blue exclusion assay; XTT assay
• Mechanism Description: Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression.

References

• Ref 1: Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine- and cisplatin-resistant models. Mol Oncol. 2024 Sep;18(9):2196-2211.