Wei Jing, Xia Song, Sun Aiqin, Qu Yaping, Gao Jinyi, Shao Genbao, Yang Wannian, Lin Qiong
School of Medicine, Jiangsu University 301 Xuefu Road, Zhenjiang 212013, Jiangsu, China.
Am J Cancer Res. 2022 Mar 15;12(3):1143-1155. eCollection 2022.
Geranylgeranylation signaling plays an important role in cancer cell proliferation. Our previous studies have shown that the YAP is one of the geranylgeranylation signal transducers in breast cancer cells (Mi W, et al., Oncogene. 2015; 34(24): 3095-3106). However, the downstream effectors that mediate the promoting effect of the geranylgeranylation/YAP signal axis on breast cancer cell proliferation remain elusive. In this report, we investigated the pathway that mediates the effect of the geranylgeranylation on breast cancer cell proliferation. The results have shown that inhibition of geranylgeranyl biosynthesis inactivates transcription of a set of kinetochore/centromere genes. Further biochemical and cell biological studies demonstrated that inhibition of geranylgeranyl biosynthesis significantly reduced the level of key kinetochore/centromere proteins, thus caused a defect in mitosis. Knockdown of YAP caused similar inhibitory effects on the kinetochore/centromere gene expression and mitosis to that of inhibition of geranylgeranyl biosynthesis. Furthermore, we found that , the gene coding for E2F1 that is known to activate expression of cell cycle genes, is a target gene of YAP. Knockdown of E2F1 also reduced expression of the kinetochore/centromere genes, suggesting that the activation effect of YAP on expression of the kinetochore/centromere genes may be mediated by E2F1. Our studies have proposed a novel geranylgeranylation-dependent cancer cell proliferation signaling pathway in which geranylgeranylation signaling promotes cancer cell mitosis via the YAP-activated transcription of kinetochore/centromere genes.
香叶基香叶基化信号传导在癌细胞增殖中起重要作用。我们之前的研究表明，YAP是乳腺癌细胞中香叶基香叶基化信号转导分子之一（Mi W等人，《癌基因》。2015年；34(24): 3095 - 3106）。然而，介导香叶基香叶基化/YAP信号轴对乳腺癌细胞增殖促进作用的下游效应器仍不清楚。在本报告中，我们研究了介导香叶基香叶基化对乳腺癌细胞增殖作用的途径。结果表明，抑制香叶基香叶基生物合成会使一组动粒/着丝粒基因的转录失活。进一步的生化和细胞生物学研究表明，抑制香叶基香叶基生物合成显著降低了关键动粒/着丝粒蛋白的水平，从而导致有丝分裂缺陷。敲低YAP对动粒/着丝粒基因表达和有丝分裂产生与抑制香叶基香叶基生物合成类似的抑制作用。此外，我们发现，已知可激活细胞周期基因表达的E2F1的编码基因是YAP的靶基因。敲低E2F1也降低了动粒/着丝粒基因的表达，表明YAP对动粒/着丝粒基因表达的激活作用可能由E2F1介导。我们的研究提出了一种新的香叶基香叶基化依赖性癌细胞增殖信号通路，其中香叶基香叶基化信号通过YAP激活的动粒/着丝粒基因转录促进癌细胞有丝分裂。
