CDK16 通过磷酸化 PRC1 促进三阴性乳腺癌的进展和转移。

CDK16 promotes the progression and metastasis of triple-negative breast cancer by phosphorylating PRC1.

机构信息

Department of Thyroid and Breast Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.

Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.

出版信息

J Exp Clin Cancer Res. 2022 Apr 21;41(1):149. doi: 10.1186/s13046-022-02362-w.

DOI:10.1186/s13046-022-02362-w

PMID:35449080

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9027050/

Abstract

BACKGROUND

Cyclin-dependent kinase 16 (CDK16) is an atypical PCTAIRE kinase, and its activity is dependent on the Cyclin Y (CCNY) family. Ccnys have been reported to regulate mammary stem cell activity and mammary gland development, and CCNY has been recognized as an oncoprotein in various cancers, including breast cancer. However, it remains unclear whether CDK16 has a role in breast cancer and whether it can be used as a therapeutic target for breast cancer.

METHODS

Publicly available breast cancer datasets analyses and Kaplan-Meier survival analyses were performed to reveal the expression and clinical relevance of atypical CDKs in breast cancer. CDK16 protein expression was further examined by immunohistochemical and immunoblot analyses of clinical samples. Cell proliferation was measured by colony formation and MTT analyses. Cell cycle and apoptosis were examined by fluorescence-activated cell sorting (FACS) analysis. Wound-healing and trans-well invasion assays were conducted to test cell migration ability. The functions of CDK16 on tumorigenesis and metastasis were evaluated by cell line-derived xenograft, patient-derived organoid/xenograft, lung metastasis and systemic metastasis mouse models. Transcriptomic analysis was performed to reveal the potential molecular mechanisms involved in the function of CDK16. Pharmacological inhibition of CDK16 was achieved by the small molecular inhibitor rebastinib to further assess the anti-tumor utility of targeting CDK16.

RESULTS

CDK16 is highly expressed in breast cancer, particularly in triple-negative breast cancer (TNBC). The elevated CDK16 expression is correlated with poor outcomes in breast cancer patients. CDK16 can improve the proliferation and migration ability of TNBC cells in vitro, and promote tumor growth and metastasis of TNBC in vivo. Both genetic knockdown and pharmacological inhibition of CDK16 significantly suppress the tumor progression of TNBC. Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis.

CONCLUSION

CDK16 plays a critical role in TNBC and is a novel promising therapeutic target for TNBC.

摘要

背景

周期蛋白依赖性激酶 16（CDK16）是一种非典型的 PCTAIRE 激酶，其活性依赖于周期蛋白 Y（CCNY）家族。已有报道称 CCNys 调节乳腺干细胞活性和乳腺发育，CCNY 已被确认为包括乳腺癌在内的各种癌症中的癌蛋白。然而，CDK16 是否在乳腺癌中发挥作用以及是否可作为乳腺癌的治疗靶点仍不清楚。

方法

通过公共乳腺癌数据集分析和 Kaplan-Meier 生存分析揭示非典型 CDK 在乳腺癌中的表达和临床相关性。通过对临床样本的免疫组化和免疫印迹分析进一步检查 CDK16 蛋白表达。通过集落形成和 MTT 分析测量细胞增殖。通过荧光激活细胞分选（FACS）分析检查细胞周期和细胞凋亡。通过划痕愈合和 Trans-well 侵袭实验检测细胞迁移能力。通过细胞系衍生的异种移植、患者衍生的类器官/异种移植、肺转移和全身转移小鼠模型评估 CDK16 对肿瘤发生和转移的功能。进行转录组分析以揭示 CDK16 功能涉及的潜在分子机制。通过小分子抑制剂 rebastinib 实现 CDK16 的药理学抑制，以进一步评估靶向 CDK16 的抗肿瘤效用。

结果

CDK16 在乳腺癌中高度表达，特别是在三阴性乳腺癌（TNBC）中。升高的 CDK16 表达与乳腺癌患者的不良预后相关。CDK16 可提高 TNBC 细胞在体外的增殖和迁移能力，并促进 TNBC 体内肿瘤生长和转移。CDK16 的基因敲低和药理学抑制均显著抑制 TNBC 的肿瘤进展。机制上，CDK16 通过磷酸化细胞分裂蛋白 1（PRC1）发挥其功能，以调节有丝分裂期间纺锤体的形成。