@article{f3c2a5280fe644e98a0c9f422ddc0a57,
title = "Keratin 23 Is a Peroxisome Proliferator-Activated Receptor Alpha–Dependent, MYC-Amplified Oncogene That Promotes Hepatocyte Proliferation",
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.",
author = "Donghwan Kim and Brocker, {Chad N.} and Shogo Takahashi and Tomoki Yagai and Taehyeong Kim and Guomin Xie and Hua Wang and Aijuan Qu and Gonzalez, {Frank J.}",
note = "Funding Information: Medical Sciences, National Institutes of Health. A. Qu was supported by National Natural Science Foundation of China (81370521, 81670400 and 91739120) and The Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions (CIT&TCD20150325). The funding sponsors had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. {\textcopyright} 2019 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.30530 Funding Information: From the 1Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; 2Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China; 3Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China. Funding Information: Received April 24, 2018; accepted January 4, 2019. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.30530/suppinfo. *Deceased. Supported by the National Cancer Institute Intramural Research Program. D.K. was supported in part by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI17C2082). C.N.B. was supported in part by the Postdoctoral Research Associate Training program through the National Institute of General Publisher Copyright: {\textcopyright} 2019 by the American Association for the Study of Liver Diseases.",
year = "2019",
month = jul,
doi = "10.1002/hep.30530",
language = "English",
volume = "70",
pages = "154--167",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "1",
}