Lu Yilu, Zheng Xulei, Hu Wei, Bian Shasha, Zhang Zhiwei, Tao Dachang, Liu Yunqiang, Ma Yongxin
Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Oncotarget. 2017 Jul 4;8(33):54913-54924. doi: 10.18632/oncotarget.18973. eCollection 2017 Aug 15.
Circadian rhythms are regulated by transcriptional and post-translational feedback loops generated by appropriate functions of clock proteins. Rhythmic degradation of the circadian clock proteins is critical for maintenance of the circadian oscillations. Notably, circadian clock does not work during spermatogenesis and can be disrupted in tumors. However, the underlying mechanism that suppresses circadian rhythms in germ cells and cancer cells remains largely unknown. Here we report that the cancer/testis antigen PIWIL2 can repress circadian rhythms both in the testis and cancer cells. By facilitating SRC binding with PI3K, PIWIL2 activates the PI3K-AKT pathway to phosphorylate and deactivate GSK3β, suppressing GSK3β-induced phosphorylation and degradation of circadian protein BMAL1 and CLOCK. Meanwhile, PIWIL2 can bind with E-Box sequences associated with the BMAL1/CLOCK complex to negatively regulate the transcriptional activation activity of promoters of clock-controlled genes. Taken together, our results first described a function for the germline-specific protein PIWIL2 in regulation of the circadian clock, providing a molecular link between spermatogenesis as well as tumorigenesis to the dysfunction of circadian rhythms.
昼夜节律由时钟蛋白的适当功能产生的转录和翻译后反馈回路调节。昼夜节律时钟蛋白的节律性降解对于维持昼夜节律振荡至关重要。值得注意的是，昼夜节律时钟在精子发生过程中不起作用，并且在肿瘤中可能被破坏。然而，抑制生殖细胞和癌细胞中昼夜节律的潜在机制在很大程度上仍然未知。在这里，我们报告癌症/睾丸抗原PIWIL2可以在睾丸和癌细胞中抑制昼夜节律。通过促进SRC与PI3K结合，PIWIL2激活PI3K-AKT途径，使GSK3β磷酸化并失活，抑制GSK3β诱导的昼夜节律蛋白BMAL1和CLOCK的磷酸化和降解。同时，PIWIL2可以与与BMAL1/CLOCK复合物相关的E-Box序列结合，以负调节时钟控制基因启动子的转录激活活性。综上所述，我们的结果首次描述了种系特异性蛋白PIWIL2在昼夜节律调节中的功能，为精子发生以及肿瘤发生与昼夜节律功能障碍之间提供了分子联系。
