Zhu Wenzhuo, Li Zhao, Xiong Liwen, Yu Xiaobo, Chen Xi, Lin Qiang
Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of medicine, Shanghai, China.
Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Theranostics. 2017 Jul 22;7(12):3078-3089. doi: 10.7150/thno.18067. eCollection 2017.
FKBP3 is a member of FK506-binding proteins (FKBPs). Little is known about the expression and functional role(s) of FKBP3 in non-small cell lung cancer (NSCLC). In the present study, we demonstrated up-regulation of FKBP3 expression, both at mRNA and protein levels, in NSCLC samples which closely correlated with poor survival in NSCLC patients. and experiments revealed that FKBP3 could promote NSCLC cell proliferation. Furthermore, knockdown of FKBP3 significantly decreased histone deacetylase 2 (HDAC2) expression and increased p27 (a cell cycle inhibitor) expression. HDAC2 modulated the acetylation of histone H3K4 by directly binding to the p27 promoter. The proliferation-promoting effect of FKBP3 was dependent on HDAC2 and inhibited by p27. Also, FKBP3 induced HDAC2 promoter activity via inhibiting the ubiquitination of transcription factor Sp1. Additionally, we identified miR-145-5p as a regulator of FKBP3. miR-145-5p overexpression suppressed cell proliferation of NSCLC cells which was abrogated by FKBP3 overexpression. Taken together, our data clearly show that FKBP3/Sp1/HDAC2/p27 control cell proliferation during NSCLC development.
FKBP3是FK506结合蛋白（FKBPs）家族的一员。目前对于FKBP3在非小细胞肺癌（NSCLC）中的表达及功能作用了解甚少。在本研究中，我们证实在NSCLC样本中，FKBP3的mRNA和蛋白水平均上调，这与NSCLC患者的不良生存密切相关。 实验表明FKBP3可促进NSCLC细胞增殖。此外，敲低FKBP3可显著降低组蛋白去乙酰化酶2（HDAC2）的表达，并增加p27（一种细胞周期抑制剂）的表达。HDAC2通过直接结合p27启动子来调节组蛋白H3K4的乙酰化。FKBP3的促增殖作用依赖于HDAC2，并受到p27的抑制。此外，FKBP3通过抑制转录因子Sp1的泛素化来诱导HDAC2启动子活性。另外，我们鉴定出miR-145-5p是FKBP3的一个调节因子。miR-145-5p的过表达抑制了NSCLC细胞的增殖，而FKBP3的过表达可消除这种抑制作用。综上所述，我们的数据清楚地表明，FKBP3/Sp1/HDAC2/p27在NSCLC发生发展过程中控制细胞增殖。
