Molecule Information

General Information of the Molecule (ID: Mol04443)

• Name: NTF2-related export protein 1 (NXT1) ,Homo sapiens
• Synonyms: Protein p15
• Molecule Type: Protein
• Gene Name: NXT1
• Gene ID: 29107
• Sequence:
  MASVDFKTYVDQACRAAEEFVNVYYTTMDKRRRLLSRLYMGTATLVWNGNAVSGQESLSE
  FFEMLPSSEFQISVVDCQPVHDEATPSQTTVLVVICGSVKFEGNKQRDFNQNFILTAQA
  S PSNTVWKIASDCFRFQDWAS
• Function: Stimulator of protein export for NES-containing proteins. Also plays a role in the nuclear export of U1 snRNA,tRNA, and mRNA . The NXF1-NXT1 heterodimer is involvedin the export of HSP70 mRNA in conjunction with ALYREF/THOC4 and THOC5. {ECO:0000269|PubMed:10567585,ECO:0000269|PubMed:10848583, ECO:0000269|PubMed:11259602,ECO:0000269|PubMed:19165146}.
• Uniprot ID: NXT1_HUMAN
• Ensembl ID: ENSG000001326614
• HGNC ID: HGNC:15913

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) 1 drug(s) in total

Lenvatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [1]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Sensitive Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: WNT/KDM5B/p15 signaling pathway; Regulation; N.A.
• In Vitro Model: B76.1/Huh7 cells; N.A.; Homo sapiens (Human); CVCL_U443
• In Vitro Model: MHCC97H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: NYG male nude mice model; Balb/c male nude mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; RNA extraction assay; RT-PCR; RNA sequencing assay; ChIP-qPCR; Immunohistochemistry
• Experiment for Drug Resistance: Viability assay
• Mechanism Description: Key results: Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib in vitro and in vivo. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib in vitro and in vivo.Conclusion and implications: AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC.

References

• Ref 1: Loss of AXIN1 regulates response to lenvatinib through a WNT/KDM5B/p15 signalling axis in hepatocellular carcinoma. Br J Pharmacol. 2025 Mar;182(6):1394-1409.