PGC7 promotes tumor oncogenic dedifferentiation through remodeling DNA methylation pattern for key developmental transcription factors.
PGC7 promotes tumor oncogenic dedifferentiation through remodeling DNA methylation pattern for key developmental transcription factors.
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PGC7 通过重塑关键发育转录因子的 DNA 甲基化模式促进肿瘤致癌去分化
DOI：
10.1038/s41418-020-00726-3
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发表时间：
2021-06
影响因子：
12.4
通讯作者：
Guan XY
中科院分区：
文献类型：
--
作者：
Yan Q;Zhang Y;Fang X;Liu B;Wong TL;Gong L;Liu S;Yu D;Liu M;Jiang L;Wang X;Wei T;Jia Y;Li L;Sun L;Tang Y;Zhou N;Yuan YF;Li Y;Ma S;Guan XY
低分化肿瘤通常表现出与其发育的前体细胞相似的表型。获得祖细胞特征的肿瘤细胞通常利用发育信号来促进癌症的进展。然而，潜在的分子事件仍然难以捉摸。在本研究中，通过对体外肝细胞分化模型的分析，发现母因子PGC7(又称DPPA3，Stella)与肝细胞癌的肝脏发育和肿瘤分化密切相关。在肝细胞成熟过程中，PGC7的表达呈下降趋势，从高分化型到低分化型逐渐增强。全基因组甲基化测序发现，PGC7可诱导发育相关基因启动子去甲基化。基于途径的网络分析表明，PGC7下游靶点可能形成与发育转录因子激活相关的网络。无论在体内还是体外，PGC7的过表达都赋予了肝癌细胞类似祖细胞的特征。机制研究表明，PGC7可以抑制uhrf1的核转位，从而促进GLI1和MYCN的启动子去甲基化，而GLI1和MYCN是肝癌自我更新和分化的重要调节因子。耗尽或抑制GLI1可有效下调MYCN的表达，阻断PGC7的作用，并使肝癌细胞对索拉非尼治疗增敏。此外，我们还发现在临床肝细胞癌患者中，PGC7与GLI1/MYCN和谱系分化标志物显著相关。PGC7的表达可能通过促进关键的发育转录因子的启动子去甲基化，促使肝癌向去分化的祖细胞方向发展；进一步抑制PGC7/GLI1/MYCN可能逆转低分化的肝癌，并提供新的治疗策略。
Poorly differentiated tumors usually exhibit phenotypes similar to that of their developmental precursor cells. Tumor cells that acquire the lineage progenitor cells feature usually exploit developmental signaling to potentiate cancer progression. However, the underlying molecular events remain elusive. In this study, based on analysis of an in vitro hepatocyte differentiation model, the maternal factor PGC7 (also known as DPPA3, STELLA) was found closely associated with liver development and tumor differentiation in hepatocellular carcinoma (HCC). Expression of PGC7 decreased during hepatocyte maturation and increased progressively from well-differentiated HCCs to poorly differentiated HCCs. Whole-genome methylation sequencing found that PGC7 could induce promoter demethylation of genes related to development. Pathway-based network analysis indicated that downstream targets of PGC7 might form networks associated with developmental transcription factor activation. Overexpression of PGC7 conferred progenitor-like features of HCC cells both in vitro and in vivo. Mechanism studies revealed that PGC7 could impede nuclear translocation of UHRF1, and thus facilitate promoter demethylation of GLI1 and MYCN, both of which are important regulators of HCC self-renewal and differentiation. Depletion or inhibition of GLI1 effectively downregulated MYCN, abolished the effect of PGC7, and sensitized HCC cells to sorafenib treatment. In addition, we found a significant correlation of PGC7 with GLI1/MYCN and lineage differentiation markers in clinical HCC patients. PGC7 expression might drive HCC toward a “dedifferentiated” progenitor lineage through facilitating promoter demethylation of key developmental transcription factors; further inhibition of PGC7/GLI1/MYCN might reverse poorly differentiated HCCs and provide novel therapeutic strategies.
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