Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.
Oncogene. 2021 Mar;40(9):1595-1608. doi: 10.1038/s41388-020-01634-z. Epub 2021 Jan 15.
KNSTRN is a component of the mitotic spindle, which was rarely investigated in tumorigenesis. AKT plays an essential role in tumorigenesis by modulating the phosphorylation of various substrates. The activation of AKT is regulated by PTEN and PIP. Here, we prove KNSTRN is positively correlated with malignancy of bladder cancer and KNSTRN activates AKT phosphorylation at Thr308 and Ser473. More importantly, our study reveals that both KNSTRN and PTEN interact with PH domain of AKT at cell membrane. The amount of KNSTRN interacted with AKT is negatively related to PTEN. Furthermore, PIP pull-down assay proves that KNSTRN promoted AKT movement to PIP. These data suggest KNSTRN may activate AKT phosphorylation by promoting AKT movement to PIP and alleviating PTEN suppression. Based on the activation of AKT phosphorylation, our study demonstrates that KNSTRN promotes bladder cancer metastasis and gemcitabine resistance in vitro and in vivo. Meanwhile, the effect of KNSTRN on tumorigenesis and gemcitabine resistance could be restored by AKT specific inhibitor MK2206 or AKT overexpression. In conclusion, we identify an oncogene KNSTRN that promotes tumorigenesis and gemcitabine resistance by activating AKT phosphorylation and may serve as a therapeutic target in bladder cancer.
KNSTRN 是有丝分裂纺锤体的一个组成部分，在肿瘤发生中很少被研究。AKT 通过调节各种底物的磷酸化在肿瘤发生中发挥重要作用。AKT 的激活受 PTEN 和 PIP 调节。在这里，我们证明 KNSTRN 与膀胱癌的恶性程度呈正相关，并且 KNSTRN 激活 AKT 在 Thr308 和 Ser473 的磷酸化。更重要的是，我们的研究揭示了 KNSTRN 和 PTEN 都在细胞膜上与 AKT 的 PH 结构域相互作用。与 AKT 相互作用的 KNSTRN 量与 PTEN 呈负相关。此外，PIP 下拉测定证明 KNSTRN 促进 AKT 向 PIP 的运动。这些数据表明，KNSTRN 可能通过促进 AKT 向 PIP 的运动并减轻 PTEN 的抑制来激活 AKT 磷酸化。基于 AKT 磷酸化的激活，我们的研究表明 KNSTRN 促进膀胱癌的体外和体内转移和吉西他滨耐药。同时，KNSTRN 对肿瘤发生和吉西他滨耐药的作用可以通过 AKT 特异性抑制剂 MK2206 或 AKT 过表达来恢复。总之，我们鉴定了一种癌基因 KNSTRN，它通过激活 AKT 磷酸化促进肿瘤发生和吉西他滨耐药，并且可能成为膀胱癌的治疗靶点。
