title: Frequent concerted genetic mechanisms disrupt multiple components of the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in thyroid cancer.
abstract: BACKGROUND
  Reactive oxygen species contribute to normal thyroid function. The NRF2 oxidative response pathway is frequently and constitutively activated in multiple tumor types, including papillary thyroid carcinoma (PTC). Genetic mechanisms underlying NRF2 pathway activation in PTC are not fully understood. Thus, we aimed to determine whether inactivating patterns of DNA-level alterations affect genes encoding for individual NRF2 inhibitor complex components (CUL3/KEAP1/RBX1) occur in PTC.
  
  
  RESULTS
  Combined patterns of epi/genetic alterations for KEAP1/CUL3/RBX1 E3 ubiquitin-ligase complex components were simultaneously interrogated for a panel of 310 PTC cases and 40 adjacent non-malignant tissues. Data were obtained from The Cancer Genome Atlas project. Enrichment of NRF2 pathway activation was assessed by gene-set enrichment analysis using transcriptome data. Our analyses revealed that PTC sustain a strikingly high frequency (80.6%) of disruption to multiple component genes of the NRF2 inhibitor complex. Hypermethylation is the predominant inactivating mechanism primarily affecting KEAP1 (70.6%) and CUL3 (20%), while copy number loss mostly affects RBX1 (16.8%). Concordantly, NRF2-associated gene expression signatures are positively and significantly enriched in PTC.
  
  
  CONCLUSIONS
  The KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is almost ubiquitously affected by multiple DNA-level mechanisms and downstream NRF2 pathway targets are activated in PTC. Given the importance of this pathway to normal thyroid function as well as to cancer; targeted inhibition of NRF2 regulators may impact strategies for therapeutic intervention involving this pathway.
authors.affiliation: BC Cancer Research Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z1L3, Canada. vmartinez@bccrc.ca.
authors.forename: Victor D
authors.initials: VD
authors.lastname: Martinez
authors.forename: Emily A
authors.initials: EA
authors.lastname: Vucic
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Pikor
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.forename: Roland
authors.initials: R
authors.lastname: Hubaux
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
mesh_terms: D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics; D002291:Carcinoma, Papillary; D002352:Carrier Proteins / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C479529:RBX1 protein, human; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases