Yu Wenjun, Qiao Yongxia, Tang Xun, Ma Lifang, Wang Yulan, Zhang Xiao, Weng Wenhao, Pan Qiuhui, Yu Yongchun, Sun Fenyong, Wang Jiayi
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Cell Signal. 2014 Dec;26(12):2961-8. doi: 10.1016/j.cellsig.2014.09.011. Epub 2014 Sep 28.
Recent studies are indicative for strong carcinogenetic roles of Runt related transcription factor 2 (Runx2) and Yes associated protein (YAP) in several cancer types. However, whether and how the interaction between Runx2 and YAP plays a role in liver tumorigenesis still remain illusive. Here, we identified a close relationship between Runx2 and YAP in liver cancer cells. Runx2 had a positive role on YAP expression and vice versa. We also found that Rux2 and YAP were capable of inhibiting long non-coding RNA (lncRNA), Metallothionein 1D, Pseudogene (MT1DP) expression through direct promoter binding. Overexpression of MT1DP resulted in reduced cell proliferation and colony formation in soft agar, but increased apoptosis in liver cancer cells, whereas knockdown of this lncRNA had the opposite effect, indicating that MT1DP acts as a tumor suppressor. Furthermore, MT1DP was revealed as a negative regulator of Alfa-fetoprotein (AFP), a classic liver cancer tumor marker, through inhibiting protein synthesis of Forkhead box A1 (FoxA1), an important transcription factor in liver development and cancer progression. Furthermore, we found that FoxA1 plays a positive role on YAP and Runx2 expression. Specially, opening the compacted chromatin by FoxA1 around CREB binding site within the YAP promoter facilitates CREB-mediated YAP transcription. Finally, MT1DP-inhibited in vivo liver cancer cell growth could be rescued by a combination of overexpression of FoxA1, Runx2 and YAP. Taken together, the close relationship between Rnux2 and YAP plays a pro-carcinogenetic role in liver cancer cells through inhibiting tumor suppressor lncRNA, MT1DP in a FoxA1 dependent manner.
近期研究表明，Runt相关转录因子2（Runx2）和Yes相关蛋白（YAP）在多种癌症类型中具有很强的致癌作用。然而，Runx2与YAP之间的相互作用是否以及如何在肝癌发生中发挥作用仍不清楚。在此，我们确定了肝癌细胞中Runx2与YAP之间的密切关系。Runx2对YAP表达具有正向作用，反之亦然。我们还发现，Rux2和YAP能够通过直接结合启动子来抑制长链非编码RNA（lncRNA）金属硫蛋白1D假基因（MT1DP）的表达。MT1DP的过表达导致肝癌细胞的增殖和软琼脂集落形成减少，但细胞凋亡增加，而敲低这种lncRNA则产生相反的效果，表明MT1DP起到肿瘤抑制因子的作用。此外，MT1DP通过抑制肝发育和癌症进展中的重要转录因子叉头框A1（FoxA1）的蛋白质合成，被揭示为甲胎蛋白（AFP，一种经典的肝癌肿瘤标志物）的负调节因子。此外，我们发现FoxA1对YAP和Runx2的表达具有正向作用。特别地，FoxA1打开YAP启动子内CREB结合位点周围的致密染色质，促进CREB介导的YAP转录。最后，FoxA1、Runx2和YAP的过表达组合可以挽救MT1DP抑制的体内肝癌细胞生长。综上所述，Rnux2与YAP之间的密切关系通过以FoxA1依赖的方式抑制肿瘤抑制性lncRNA MT1DP，在肝癌细胞中发挥促癌作用。
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