Up-regulation of cancer-related genes in HepG2 cells by TCDD requires PRMT I and IV

Abstract

The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a well-known carcinogen, however, the biological mechanism of carcinogenesis by TCDD has not been established. Recently, protein arginine methyltransferases (PRMTs) have been identified as secondary transcription co-activators and are proposed to be co-activators of aryl hydrocarbon receptors binding to xenobiotic response elements. Both PRMT1 and PRMT4 were also reported to be involved with carcinogenesis. The aim of this study was to identify cancer-related genes that are regulated by TCDD exposure and the effect of arginine methylation on TCDD toxicity by transfecting human hepatocarcinoma cells with PRMT1 and PRMT4 siRNA. By micro-array analysis, 1,461 genes were up-regulated and 1,591 genes were down-regulated by TCDD exposure. Among the 16 up-regulated genes which had functions related to cancer or metastasis, 13 genes were confirmed by quantitative real time RT-PCR: ABCG2, NRP1, SOX5, BIRC3, CD109, CYP1A1, ERBB2, MTA1, FURIN, F3, PIK3R3, NPTN and NTN4. Co-inhibition of PRMT1 and PRMT4 resulted in decreased expression of eight of these genes, MTA1, ERBB2, SOX5, CD 109, FURIN, NRP1, PIK3R3 and ABCG2, all of which have been reportedly involved in breast, ovary, prostate and lung cancers, and metastasis.