Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
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.
Hepatology. 2019 Jul;70(1):154-167. doi: 10.1002/hep.30530. Epub 2019 Mar 20.
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 (Myc ) 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 Myc 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.
过氧化物酶体增殖物激活受体α（PPARA）的慢性激活可促进小鼠的 MYC 相关肝细胞癌（HCC）。最近的研究表明，MYC 可以作为转录的放大器发挥作用，其中 MYC 不作为基因表达的“开-关”开关，而是通过刺激转录延伸来加速活性启动子处的转录率。考虑到 MYC 可能会放大 PPARA 靶基因的表达以增强细胞增殖和肝癌的可能性，我们分析了用 PPARA 激动剂吡格列酮处理的野生型和肝特异性 Myc 敲除（Myc）小鼠肝脏中的基因表达。在存在 MYC 的情况下，一组 PPARA 靶基因被扩增，包括角蛋白 23（Krt23）。在 Myc 小鼠中，Krt23 的诱导明显减弱，在 Ppara 缺失小鼠中完全消除。报告基因测定和染色质免疫沉淀证实了 PPARA 和 MYC 直接结合到 Krt23 启动子内的位点。在原代肝细胞中强制表达 KRT23 诱导细胞周期相关基因。这些数据表明，PPARA 激活可升高 MYC 表达，进而增强参与细胞增殖的特定 PPARA 靶基因的表达。最后，KRT23 蛋白在人类 HCC 中高度升高。结论：这些结果表明，MYC 介导的特定 PPARA 靶基因，如 Krt23 的转录增强可能消除了肝细胞生长和增殖的限速限制，导致肝癌。
