Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
China-US (Henan) Hormel Cancer Institute, No. 127, Dongming Road, Jinshui District, Zhengzhou, Henan, China.
Cell Death Differ. 2022 Jan;29(1):14-27. doi: 10.1038/s41418-021-00828-6. Epub 2021 Jul 14.
Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related deaths. However, there are few effective therapeutic targets for CRC patients. Here, we found that CDK15 was highly expressed in human CRC and negatively correlated with patient prognosis and overall survival in tissue microarray. Knockdown of CDK15 suppressed cell proliferation and anchorage-independent growth of CRC cells and inhibited tumor growth in cell line-derived xenograft (CDX) model. Importantly, knockout of CDK15 in mice retarded AOM/DSS-induced tumorigenesis and CDK15 silencing by lentivirus significantly suppressed tumor progression in patient-derived xenograft (PDX) model. Mechanistically, CDK15 could bind PAK4 and phosphorylate PAK4 at S291 site. Phosphorylation of PAK4 at the S291 residue promoted cell proliferation and anchorage-independent growth through β-catenin/c-Myc, MEK/ERK signaling pathway in CRC. Moreover, inhibition of PAK4 reversed the tumorigenic function of CDK15 in CRC cells and pharmacological targeting PAK4 suppressed tumor growth in PDX models. Thus, our data reveal the pivotal role of CDK15 in CRC progression and demonstrate CDK15 promotes CRC tumorigenesis by phosphorylating PAK4. Hence, the CDK15-PAK4 axis may serve as a novel therapeutic target for CRC.
结直肠癌（CRC）是第三大常见癌症，也是癌症相关死亡的第二大主要原因。然而，CRC 患者的有效治疗靶点很少。在这里，我们发现 CDK15 在人 CRC 中高度表达，与组织微阵列中患者的预后和总生存期呈负相关。CDK15 的敲低抑制了 CRC 细胞的增殖和锚定非依赖性生长，并抑制了细胞系衍生异种移植（CDX）模型中的肿瘤生长。重要的是，CDK15 在小鼠中的敲除延缓了 AOM/DSS 诱导的肿瘤发生，而慢病毒介导的 CDK15 沉默显著抑制了患者来源异种移植（PDX）模型中的肿瘤进展。在机制上，CDK15 可以与 PAK4 结合，并在 S291 位点磷酸化 PAK4。CRC 中 S291 残基上 PAK4 的磷酸化通过 β-catenin/c-Myc、MEK/ERK 信号通路促进细胞增殖和锚定非依赖性生长。此外，抑制 PAK4 逆转了 CDK15 在 CRC 细胞中的致瘤功能，药物靶向 PAK4 抑制了 PDX 模型中的肿瘤生长。因此，我们的数据揭示了 CDK15 在 CRC 进展中的关键作用，并证明 CDK15 通过磷酸化 PAK4 促进 CRC 肿瘤发生。因此，CDK15-PAK4 轴可能成为 CRC 的一个新的治疗靶点。
