A tumor suppressor enhancing module orchestrated by GATA4 denotes a therapeutic opportunity for GATA4 deficient HCC patients
A tumor suppressor enhancing module orchestrated by GATA4 denotes a therapeutic opportunity for GATA4 deficient HCC patients
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GATA4 精心策划的肿瘤抑制增强模块为 GATA4 缺陷型 HCC 患者提供了治疗机会
DOI：
10.7150/thno.38060
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Chen, Liang
中科院分区：
文献类型：
--
作者：
Lu, Feng;Zhou, Qian;Chen, Liang
原理：有效的靶向治疗在肝细胞癌（HCC）临床中受到限制。肿瘤抑制基因（TSGs）的特性和阐明其信号级联可能为肝癌的靶向治疗提供新的策略。方法：我们检查了HCC样本的全基因组DNA拷贝数变异（CNV），重点是TSG候选者的缺失基因。收集临床数据、体外和体内数据以验证肿瘤抑制功能。结果：肝癌组织中GATA 4基因位点的局灶性缺失是最显著的特征。GATA 4的异位表达导致HCC细胞系的衰老。从机制上讲，GATA 4通过协调肿瘤抑制增强模块的组装来发挥肿瘤抑制作用：GATA 4直接结合并有效抑制β-catenin的mRNA转录活性;同时，β-catenin被GATA 4募集到启动子区域并促进GATA 4靶基因（其本身是TSG）的转录。GATA 4的表达在体内可有效缩小GATA 4缺陷型HCC肿瘤。我们还发现β-catenin抑制剂能够缩小GATA 4缺陷的肿瘤。结论：我们的研究揭示了一个以前未被注意的肿瘤抑制增强模块组装异位表达的GATA 4在肝癌细胞中，并表示GATA 4缺陷肝癌患者的治疗机会。我们的研究还提出了一个有趣的情况下，一个致癌转录因子有条件地作为一个肿瘤抑制因子时，招募的TSG转录因子。
Rationale: Effective targeting therapies are limited in Hepatocellular carcinoma (HCC) clinic. Characterization of tumor suppressor genes (TSGs) and elucidation their signaling cascades could shed light on new strategies for developing targeting therapies for HCC. Methods: We checked genome-wide DNA copy number variation (CNV) of HCC samples, focusing on deleted genes for TSG candidates. Clinical data, in vitro and in vivo data were collected to validate the tumor suppressor functions. Results: Focal deletion of GATA4 gene locus was the most prominent feature across all liver cancer samples. Ectopic expression of GATA4 resulted in senescence of HCC cell lines. Mechanistically, GATA4 exerted tumor suppressive role by orchestrating the assembly of a tumor suppressor enhancing module: GATA4 directly bound and potently inhibited the mRNA transcription activity of β-catenin; meanwhile, β-catenin was recruited by GATA4 to promoter regions and facilitated transcription of GATA4 target genes, which were TSGs per se. Expression of GATA4 was effective to shrink GATA4-deficient HCC tumors in vivo. We also showed that β-catenin inhibitor was capable of shrinking GATA4-deficient tumors. Conclusions: Our study unveiled a previously unnoticed tumor suppressor enhancing module assembled by ectopically expressed GATA4 in HCC cells and denoted a therapeutic opportunity for GATA4 deficient HCC patients. Our study also presented an interesting case that an oncogenic transcription factor conditionally functioned as a tumor suppressor when recruited by a TSG transcription factor.