Keratin 23 Is a Peroxisome Proliferator-Activated Receptor Alpha-Dependent, MYC-Amplified Oncogene That Promotes Hepatocyte Proliferation
Keratin 23 Is a Peroxisome Proliferator-Activated Receptor Alpha-Dependent, MYC-Amplified Oncogene That Promotes Hepatocyte Proliferation
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角蛋白 23 是一种过氧化物酶体增殖物激活受体 Alpha 依赖性、MYC 扩增癌基因，可促进肝细胞增殖
DOI：
10.1002/hep.30530
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发表时间：
2019-07-01
期刊：
影响因子：
13.5
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
--
作者：
Kim, Donghwan;Brocker, Chad N.;Gonzalez, Frank J.
核受体过氧化物酶体增殖物激活受体α（PPARA）的慢性激活促进小鼠MYC连锁肝细胞癌（HCC）。最近的研究表明，MYC可以作为转录的放大器，其中MYC不作为基因表达的“开-关”开关，而是通过刺激转录物延伸来加速活性启动子处的转录速率。考虑到MYC可能扩增PPARA靶基因的表达以增强细胞增殖和肝癌的可能性，从用PPARA激动剂吡啉烟酸处理的野生型和肝脏特异性Myc敲除（Myc（Delta Hep））小鼠的肝脏分析基因表达。在MYC存在下扩增PPARA靶基因的子集，包括角蛋白23（Krt 23）。Krt 23的诱导在Myc（Delta Hep）小鼠中显著减弱，并且在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PPARA和MYC直接结合到Krt 23启动子内的位点。原代肝细胞中KRT 23的强制表达诱导细胞周期相关基因。这些数据表明，PPARA活化提高MYC表达，这反过来又增强了参与细胞增殖的选择PPARA靶基因的表达。最后，KRT 23蛋白在人类HCC中高度升高。结论：这些结果表明，MYC介导的选择PPARA靶基因（如Krt 23）的转录增强可能会消除对肝细胞生长和增殖的限速限制，从而导致肝癌。
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(Delta Hep)) 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(Delta Hep) 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.