FRMD8靶向CDK4活化和RB降解以抑制结肠癌生长。
FRMD8 targets both CDK4 activation and RB degradation to suppress colon cancer growth.
发表日期：2023 Jul 31
作者：
Miao Yu, Weijie Wu, Yi Sun, Haoyi Yan, Lei Zhang, Zhenbin Wang, Yuqing Gong, Tianzhuo Wang, Qianchen Li, Jiagui Song, Mengyuan Wang, Jing Zhang, Yan Tang, Jun Zhan, Hongquan Zhang
来源：
Cell Reports
摘要：
细胞周期蛋白依赖激酶4（CDK4）和视网膜母细胞瘤蛋白（RB）是两个在不同场景中发挥重要细胞周期调节作用的蛋白。在此，我们报道了富含FERM结构域的8号蛋白（FRMD8）通过抑制CDK4的活化和稳定RB的方式来导致细胞周期停滞，并抑制结肠直肠癌（CRC）细胞生长。FRMD8分别与CDK7和CDK4发生相互作用，并干扰CDK7与CDK4的相互作用，从而进一步抑制CDK4的活化。FRMD8与MDM2竞争结合RB，并减弱MDM2介导的RB降解。在小鼠中Frmd8缺失会加速氧化甲烷/右旋糖苷硫酸钠诱导的结肠腺瘤形成。FRMD8启动子发生高甲基化，并且FRMD8的低表达预示着CRC患者预后不良。此外，我们发现一个含有LKCHE的FRMD8肽段可以阻断MDM2与RB的结合并稳定RB。同时应用CDK4抑制剂和FRMD8肽的联合治疗可显著抑制CRC细胞生长。因此，利用含有LKCHE的肽段干预MDM2-RB相互作用在CDK4/6抑制剂耐药患者中可能具有治疗价值。版权所有©2023作者。由Elsevier Inc.出版。保留所有权利。
Cyclin-dependent kinase 4 (CDK4) and retinoblastoma protein (RB) are both important cell-cycle regulators that function in different scenarios. Here, we report that FERM domain-containing 8 (FRMD8) inhibits CDK4 activation and stabilizes RB, thereby causing cell-cycle arrest and inhibiting colorectal cancer (CRC) cell growth. FRMD8 interacts separately with CDK7 and CDK4, and it disrupts the interaction of CDK7 with CDK4, subsequently inhibiting CDK4 activation. FRMD8 competes with MDM2 to bind RB and attenuates MDM2-mediated RB degradation. Frmd8 deficiency in mice accelerates azoxymethane/dextran-sodium-sulfate-induced colorectal adenoma formation. The FRMD8 promoter is hypermethylated, and low expression of FRMD8 predicts poor prognosis in CRC patients. Further, we identify an LKCHE-containing FRMD8 peptide that blocks MDM2 binding to RB and stabilizes RB. Combined application of the CDK4 inhibitor and FRMD8 peptide leads to marked suppression of CRC cell growth. Therefore, using an LKCHE-containing peptide to interfere with the MDM2-RB interaction may have therapeutic value in CDK4/6 inhibitor-resistant patients.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.