Donghwan Kim1, Chad N Brocker1, Shogo Takahashi1, Tomoki Yagai1, Taehyeong Kim1, Guomin Xie2, Hua Wang3, Aijuan Qu2, Frank J Gonzalez1. 1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China. 3. Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
Abstract
Chronic activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes MYC-linked hepatocellular carcinoma (HCC) in mice. Recent studies have shown that MYC can function as an amplifier of transcription where MYC does not act as an "on-off" switch for gene expression but rather accelerates transcription rates at active promoters by stimulating transcript elongation. Considering the possibility that MYC may amplify the expression of PPARA target genes to potentiate cell proliferation and liver cancer, gene expression was analyzed from livers of wild-type and liver-specific Myc knockout (MycΔHep ) mice treated with the PPARA agonist pirinixic acid. A subset of PPARA target genes was amplified in the presence of MYC, including keratin 23 (Krt23). The induction of Krt23 was significantly attenuated in MycΔHep mice and completely abolished in Ppara-null mice. Reporter gene assays and chromatin immunoprecipitation confirmed direct binding of both PPARA and MYC to sites within the Krt23 promoter. Forced expression of KRT23 in primary hepatocytes induced cell cycle-related genes. These data indicate that PPARA activation elevates MYC expression, which in turn potentiates the expression of select PPARA target genes involved in cell proliferation. Finally, KRT23 protein is highly elevated in human HCCs. Conclusion: These results revealed that MYC-mediated transcriptional potentiation of select PPARA target genes, such as Krt23, may remove rate-limiting constraints on hepatocyte growth and proliferation leading to liver cancer.
Chronic activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes MYC-linked hepatocellular carcinoma (HCC) in mice. Recent studies have shown that MYC can function as an amplifier of transcription where MYC does not act as an "on-off" switch for gene expression but rather accelerates transcription rates at active promoters by stimulating transcript elongation. Considering the possibility that MYC may amplify the expression of PPARA target genes to potentiate cell proliferation and liver cancer, gene expression was analyzed from livers of wild-type and liver-specific Myc knockout (MycΔHep ) mice treated with the PPARA agonist pirinixic acid. A subset of PPARA target genes was amplified in the presence of MYC, including keratin 23 (Krt23). The induction of Krt23 was significantly attenuated in MycΔHep mice and completely abolished in Ppara-null mice. Reporter gene assays and chromatin immunoprecipitation confirmed direct binding of both PPARA and MYC to sites within the Krt23 promoter. Forced expression of KRT23 in primary hepatocytes induced cell cycle-related genes. These data indicate that PPARA activation elevates MYC expression, which in turn potentiates the expression of select PPARA target genes involved in cell proliferation. Finally, KRT23 protein is highly elevated in human HCCs. Conclusion: These results revealed that MYC-mediated transcriptional potentiation of select PPARA target genes, such as Krt23, may remove rate-limiting constraints on hepatocyte growth and proliferation leading to liver cancer.
Authors: Peter B Rahl; Charles Y Lin; Amy C Seila; Ryan A Flynn; Scott McCuine; Christopher B Burge; Phillip A Sharp; Richard A Young Journal: Cell Date: 2010-04-30 Impact factor: 41.582
Authors: I M de Alboran; R C O'Hagan; F Gärtner; B Malynn; L Davidson; R Rickert; K Rajewsky; R A DePinho; F W Alt Journal: Immunity Date: 2001-01 Impact factor: 31.745
Authors: Chi V Dang; Kathryn A O'Donnell; Karen I Zeller; Tam Nguyen; Rebecca C Osthus; Feng Li Journal: Semin Cancer Biol Date: 2006-07-25 Impact factor: 15.707
Authors: Sven-T Liffers; Abdelouahid Maghnouj; Johanna B Munding; René Jackstadt; Ulrike Herbrand; Thomas Schulenborg; Katrin Marcus; Susanne Klein-Scory; Wolff Schmiegel; Irmgard Schwarte-Waldhoff; Helmut E Meyer; Kai Stühler; Stephan A Hahn Journal: BMC Cancer Date: 2011-04-14 Impact factor: 4.430
Authors: Volker Kinast; Stefan L Leber; Richard J P Brown; Gabrielle Vieyres; Patrick Behrendt; Constanze Eßbach; Pavel Strnad; Florian W R Vondran; Markus Cornberg; Cora Wex; Thomas Pietschmann; Johannes Haybaeck; Daniel Todt; Eike Steinmann Journal: Cells Date: 2019-06-18 Impact factor: 6.600