IKBIP, a novel glioblastoma biomarker, maintains abnormal proliferation of tumor cells by inhibiting the ubiquitination and degradation of CDK4

Kaishu Li; Guanglong Huang; Ziyu Wang; Runwei Yang; Wanghao Zhang; Bowen Ni; Jingyu Guan; Guozhong Yi; Zhiyong Li; Qihui Zhu; Qian Peng; Lunhao Yang; Ling Qi; Yawei Liu

doi:10.1016/j.bbadis.2022.166571

IKBIP, a novel glioblastoma biomarker, maintains abnormal proliferation of tumor cells by inhibiting the ubiquitination and degradation of CDK4

Biochim Biophys Acta Mol Basis Dis. 2023 Jan 1;1869(1):166571. doi: 10.1016/j.bbadis.2022.166571. Epub 2022 Oct 14.

Authors

Kaishu Li¹, Guanglong Huang², Ziyu Wang³, Runwei Yang², Wanghao Zhang², Bowen Ni³, Jingyu Guan⁴, Guozhong Yi², Zhiyong Li², Qihui Zhu⁵, Qian Peng⁵, Lunhao Yang⁵, Ling Qi⁶, Yawei Liu⁷

Affiliations

¹ Department of Neurosurgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, China; Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Institute of digestive disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, China.
² Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
³ Department of Neurosurgery & Medical Research Center, Shunde Hospital, Southern Medical University, Shunde 528300, China.
⁴ Department of Neurosurgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, China.
⁵ Institute of digestive disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, China.
⁶ Department of Neurosurgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, China; Institute of digestive disease of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, China. Electronic address: qiling1718@gzhmu.edu.cn.
⁷ Department of Neurosurgery & Medical Research Center, Shunde Hospital, Southern Medical University, Shunde 528300, China. Electronic address: liuyawei@smu.edu.cn.

PMID: 36244542
DOI: 10.1016/j.bbadis.2022.166571

Abstract

Sustained proliferative signaling is a crucial hallmark and therapeutic target in glioblastoma (GBM); however, new intrinsic regulators and their underlying mechanisms remain to be elucidated. In this study, I kappa B kinase interacting protein (IKBIP) was identified to be correlated with the progression of GBM by analysis of The Cancer Genome Atlas (TCGA) data. TCGA database analysis indicated that higher IKBIP expression was associated with high tumor grade and poor prognosis in GBM patients, and these correlations were subsequently validated in clinical samples. IKBIP knockdown induced G1/S arrest by blocking the Cyclin D1/CDK4/CDK6/CDK2 pathway. Our results showed that IKBIP may bind directly to CDK4, a key cell cycle checkpoint protein, and prevent its ubiquitination-mediated degradation in GBM cells. An in vivo study confirmed that IKBIP knockdown strongly suppressed cell proliferation and tumor growth and prolonged survival in a mouse xenograft model established with human GBM cells. In conclusion, IKBIP functions as a novel driver of GBM by binding and stabilizing the CDK4 protein. IKBIP could be a potential therapeutic target in GBM.

Keywords: CDK4; Cell cycle; Glioblastoma; IKBIP; Ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers / metabolism
Brain Neoplasms* / metabolism
Cell Proliferation
Cyclin-Dependent Kinase 4 / genetics
Cyclin-Dependent Kinase 4 / metabolism
Glioblastoma* / metabolism
Humans
Mice
Ubiquitination

Substances

Biomarkers
CDK4 protein, human
Cyclin-Dependent Kinase 4
IKBIP protein, human

Associated data

figshare/10.6084/m9.figshare.19807618