title: Transporter gene expression in human head and neck squamous cell carcinoma and associated epigenetic regulatory mechanisms.
abstract: Expression levels of membrane transporters may affect the disposition, and thereby treatment efficacy, of anticancer drugs in human head and neck squamous cell carcinoma (HNSCC). Herein, we analyzed the gene expression profile of membrane transporters in HNSCC. In addition, we evaluated the mechanisms of transporter regulation in HNSCC and focused on the role of the nuclear pregnane X receptor (or NR1I2) and epigenetic mechanisms. Real-time RT-PCR revealed a significantly increased mRNA expression of membrane transporters SLCO1A2 and SLCO1B3 and a significantly decreased expression of transporters SLCO2B1, SLCO2A1, and ABCC3 in human HNSCC tumors compared with adjacent normal mucosa. An association between SLCO2B1 mRNA levels in tumors and 5-year survival of patients with HNSCC was observed (χ2 = 6.59, P = 0.010). Bisulfite sequencing revealed that promoter CpG islands of ABCC3 and SLCO2A1 were not hypermethylated, indicating that these genes were not epigenetically silenced in HNSCC tumors. In HNSCC-derived cell lines, transcript expression of transporters (e.g., ABCC3 or SLCO2A1; P < 0.001 for both) and NR1I2 (P < 0.001) was markedly induced by the DNA methyltransferase inhibitor, decitabine. Cotreatment with the prototypical pregnane X receptor activator, rifampicin, significantly reversed decitabine-induced ABCC3 and SLCO2A1 expression. In summary, the expression of drug transporters (i) is markedly changed in HNSCC tumor tissues compared with normal mucosa, (ii) might be predictive of the outcome of patients with HNSCC, and (iii) is affected by novel epigenetic therapies and is further modulated by nuclear receptor-mediated mechanisms.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Zolk@pharmakologie.med.uni-erlangen.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schnepf
authors.forename: Marc
authors.initials: M
authors.lastname: Muschler
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Olaf
authors.initials: O
authors.lastname: Wendler
authors.forename: Maximilian
authors.initials: M
authors.lastname: Traxdorf
authors.forename: Heinrich
authors.initials: H
authors.lastname: Iro
authors.forename: Johannes
authors.initials: J
authors.lastname: Zenk
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000378:metabolism; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D026901:Membrane Transport Proteins; C000625852:NR1I2 protein, human; D009363:Neoplasm Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011987:Receptors, Steroid