FRMD8 targets both CDK4 activation and RB degradation to suppress colon cancer growth.
FRMD8 targets both CDK4 activation and RB degradation to suppress colon cancer growth.
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DOI：
10.1016/j.celrep.2023.112886
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发表时间：
2023-07
期刊：
影响因子：
8.8
通讯作者：
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;J. Zhan;Hongquan Zhang
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文献类型：
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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;J. Zhan;Hongquan Zhang
细胞周期蛋白依赖性激酶4（CDK 4）和视网膜母细胞瘤蛋白（RB）都是重要的细胞周期调节因子，在不同的情况下发挥作用。在这里，我们报告说，FERM域包含8（FRMD 8）抑制CDK 4激活和稳定RB，从而导致细胞周期停滞和抑制结直肠癌（CRC）细胞生长。FRMD 8分别与CDK 7和CDK 4相互作用，并破坏CDK 7与CDK 4的相互作用，随后抑制CDK 4活化。FRMD 8与MDM 2竞争结合RB并减弱MDM 2介导的RB降解。小鼠frmd 8缺陷加速氧化偶氮甲烷/葡聚糖硫酸钠诱导的结直肠腺瘤形成。FRMD 8启动子高甲基化，FRMD 8低表达预示CRC患者预后不良。此外，我们鉴定了含有LKCHE的FRMD 8肽，其阻断MDM 2与RB的结合并稳定RB。CDK 4抑制剂和FRMD 8肽的组合应用导致CRC细胞生长的显著抑制。因此，使用含LKCHE的肽干扰MDM 2-RB相互作用可能在CDK 4/6受体耐药患者中具有治疗价值。
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. TheFRMD8promoter 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.