title: Transcriptome profiling and genome-wide DNA binding define the differential role of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells.
abstract: Fenretinide is significantly more effective in inducing apoptosis in cancer cells than all-trans retinoic acid (ATRA). The current study uses a genome-wide approach to understand the differential role fenretinide and ATRA have in inducing apoptosis in Huh7 cells. Fenretinide and ATRA-induced gene expressions and DNA bindings were profiled using microarray and chromatin immunoprecipitation with anti-RXRα antibody. The data showed that fenretinide was not a strong transcription regulator. Fenretinide only changed the expressions of 1 093 genes, approximately three times less than the number of genes regulated by ATRA (2 811). Biological function annotation demonstrated that both fenretinide and ATRA participated in pathways that determine cell fate and metabolic processes. However, fenretinide specifically induced Fas/TNFα-mediated apoptosis by increasing the expression of pro-apoptotic genes i.e., DEDD2, CASP8, CASP4, and HSPA1A/B; whereas, ATRA induced the expression of BIRC3 and TNFAIP3, which inhibit apoptosis by interacting with TRAF2. In addition, fenretinide inhibited the expression of the genes involved in RAS/RAF/ERK-mediated survival pathway. In contrast, ATRA increased the expression of SOSC2, BRAF, MEK, and ERK genes. Most genes regulated by fenretinide and ATRA were bound by RXRα, suggesting a direct effect. This study revealed that by regulating fewer genes, the effects of fenretinide become more specific and thus has fewer side effects than ATRA. The data also suggested that fenretinide induces apoptosis via death receptor effector and by inhibiting the RAS/RAF/ERK pathway. It provides insight on how retinoid efficacy can be improved and how side effects in cancer therapy can be reduced.
authors: Department of Medical Pathology and Laboratory Medicine, 4645 2nd Ave, Research Building III, University of California, Davis Health Systems, Sacramento, CA 95817, USA. yinghu0821@gmail.com
authors: Ying
authors: Y
authors: Hu
authors: Hui-Xin
authors: HX
authors: Liu
authors: Yuqi
authors: Y
authors: He
authors: Yaping
authors: Y
authors: Fang
authors: Jianwen
authors: J
authors: Fang
authors: Yu-Jui Yvonne
authors: YJ
authors: Wan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D017313:Fenretinide / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D014212:Tretinoin / Q000494:pharmacology*; D048490:raf Kinases / Q000502:physiology; D018631:ras Proteins / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D047490:Retinoid X Receptor alpha; D017313:Fenretinide; D014212:Tretinoin; D004247:DNA; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins
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