FRMD8 targets both CDK4 activation and RB degradation to suppress colon cancer growth

• Published in: Cell reports (Cambridge) Vol. 42; no. 8; p. 112886
• Main Authors: Yu, Miao, Wu, Weijie, Sun, Yi, Yan, Haoyi, Zhang, Lei, Wang, Zhenbin, Gong, Yuqing, Wang, Tianzhuo, Li, Qianchen, Song, Jiagui, Wang, Mengyuan, Zhang, Jing, Tang, Yan, Zhan, Jun, Zhang, Hongquan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29-08-2023; Elsevier
• Subjects: CDK4; CP: Cancer; CP: Molecular biology; CRC; FRMD8; MDM2; RB; FRMD8; CDK4; CRC; CP: Cancer; MDM2; CP: Molecular biology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112886

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.
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•FRMD8 prevents CDK7-mediated CDK4 activation and stabilizes RB•FRMD8 deficiency accelerates AOM/DSS-induced colorectal adenoma formation•Low expression of FRMD8 predicts a poor prognosis in CRC patients•The LKCHE-containing peptide inhibits cell proliferation by stabilizing RB
Yu et al. report on a colorectal tumor-suppressive protein, FRMD8, which acts as a specific intrinsic inhibitor of CDK4 and an effective RB stabilizer, thereby inhibiting cell-cycle progression and CRC cell proliferation. The LKCHE-containing peptide may be of therapeutic value.