Transcriptional activation of CBF\u03b2 by CDK11p110 is necessary to promote osteosarcoma cell proliferation

Yong Feng,Zengwu Shao,Jacson Shen,Francis Hornicek,Jianming Zhang,Zhenfeng Duan,Yunfei Liao

doi:10.1186/s12964-019-0440-5

Abstract

BackgroundAberrant expression of cyclin-dependent protein kinases (CDK) is a hallmark of cancer. CDK11 plays a crucial role in cancer cell growth and proliferation. However, the molecular mechanisms of CDK11 and CDK11 transcriptionally regulated genes are largely unknown.MethodsIn this study, we performed a global transcriptional analysis using gene array technology to investigate the transcriptional role of CDK11 in osteosarcoma. The promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay were used to identify direct transcriptional targets of CDK11. Clinical relevance and function of core-binding factor subunit beta (CBFβ) were further accessed in osteosarcoma.ResultsWe identified a transcriptional role of protein-DNA interaction for CDK11p110, but not CDK11p58, in the regulation of CBFβ expression in osteosarcoma cells. The CBFβ promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay confirmed that CBFβ is a direct transcriptional target of CDK11. High expression of CBFβ is associated with poor outcome in osteosarcoma patients. Expression of CBFβ contributes to the proliferation and metastatic behavior of osteosarcoma cells.ConclusionsThese data establish CBFβ as a mediator of CDK11p110 dependent oncogenesis and suggest that targeting the CDK11- CBFβ pathway may be a promising therapeutic strategy for osteosarcoma treatment.Graphical

Highlights

Aberrant expression of cyclin-dependent protein kinases (CDK) is a hallmark of cancer
We identified CDK11p110, but not CDK11p58, in the transcriptional regulation of core-binding factor subunit beta (CBFβ) expression in osteosarcoma cells, which is important for bone cell development and formation of the skeleton
Expression profiling of gene regulation by Cyclin-dependent protein kinase 11 (CDK11) To identify the genes regulated in response to knockdown of CDK11 expression, KHOS and U-2OS osteosarcoma cell lines were transfected with CDK11 Small interfering RNA (siRNA) and their gene expression profiles were analyzed by Genesifter

Summary

Introduction

Aberrant expression of cyclin-dependent protein kinases (CDK) is a hallmark of cancer. CDK11 plays a crucial role in cancer cell growth and proliferation. It has been well established that overexpression and activation of cyclin-dependent kinases (CDK) is a hallmark of human cancer [1, 2]. The Food and Drug Administration (FDA) has approved the CDK4/6 inhibitors Palbociclib, Ribociclib and Abemaciclib for treating metastatic breast cancer. These inhibitors have demonstrated promising antitumor potentials both as a monotherapy and in combined therapy in numerous clinical trials [3,4,5,6]. CDK11 plays a crucial role in cell proliferation and growth of cancers, such as breast cancer, ovarian.

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