AURKA Increase the Chemosensitivity of Colon Cancer Cells to Oxaliplatin by Inhibiting the TP53-Mediated DNA Damage Response Genes.

Baocong Shan,Jian Zhou,Weiwei Yang,Yiqi Wu,Guangyou Wang,Yang Zhang,Xiaoyu Qi,Xiaobo Li,Minghui Zhang,Yuanyuan Zhu,Ran Zhao,Tianzhen Wang,Jinan Gong

doi:10.1155/2020/8916729

Abstract

AURKA, a cell cycle-regulated kinase, is associated with malignant transformation and progression in many cancer types. We analyzed the expression change of AURKA in pan-cancer and its effect on the prognosis of cancer patients using the TCGA dataset. We revealed that AURKA was extensively elevated and predicted a poor prognosis in most of the detected cancer types, with an exception in colon cancer. AURKA was elevated in colon cancer, but the upregulation of AURKA indicated better outcomes of colon cancer patients. Then we revealed that undermethylation of the AURKA gene and several transcription factors contributed to the upregulation of AURKA in colon cancer. Moreover, we demonstrated that AURKA overexpression promoted the death of colon cancer cells induced by Oxaliplatin, whereas knockdown of AURKA significantly weakened the chemosensitivity of colon cancer cells to Oxaliplatin. Mechanistically, AURKA inhibited DNA damage response by suppressing the expression of various DNA damage repair genes in a TP53-dependent manner, which can partly explain that ARUKA is associated with a beneficial outcome of colon cancer. This study provided a possibility to use AURKA as a biomarker to predict the chemosensitivity of colon cancer to platinum in the clinic.

Highlights

Aurora Kinase A (AURKA) is a cell cycle-regulated kinase involved in centrosome maturation, mitotic entry, bipolar spindle assembly, and chromosome separation [1]
The data of AURKA mRNA expression in 18 types of cancers and matched normal tissues were downloaded from The Cancer Genome Atlas (TCGA) database, including Bladder Urothelial Carcinoma (BLCA), Breast Invasive Carcinoma (BRCA), Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC), Colon Adenocarcinoma (COAD), Head and Neck Squamous Cell Carcinoma (HNSC), Kidney Renal Clear Cell Carcinoma (KIRC), Kidney Renal Papillary Cell Carcinoma (KIRP), Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), Lung Squamous Cell Carcinoma (LUSC), Pancreatic Adenocarcinoma (PAAD), Prostate Adenocarcinoma (PRAD), Rectum Adenocarcinoma (READ), Sarcoma (SARC), Skin Cutaneous Melanoma (SKCM), Stomach Adenocarcinoma (STAD), Thyroid Carcinoma (THCA), and Uterine Corpus Endometrial Carcinoma (UCEC)
We showed that the AURKA level was adversely correlated with overall survival (OS) in 5 of 15 cancers, including LUAD, KIRP, PAAD, SKCM, and LIHC

Summary

Introduction

Aurora Kinase A (AURKA) is a cell cycle-regulated kinase involved in centrosome maturation, mitotic entry, bipolar spindle assembly, and chromosome separation [1]. The elevated expression of AURKA is frequently reported in many cancer types [2]. AURKA, alone or combined with other factors, can trigger cell malignant transformation [3, 4] and promote the malignant phenotype of cancer cells [5, 6]. AURKA shows oncogenic activity by regulating multiple oncogenic and tumor-suppressive proteins [7]. Of these proteins, tumor suppressor TP53 has been intensively studied. Phosphorylation of TP53 at Ser215 and Ser315 by AURKA results in TP53 degradation by MDM2-mediated ubiquitination and abrogation of TP53 DNA binding/ transactivation activity, respectively [8, 9]. Negative feedback regulation between AURKA and TP53 greatly promotes carcinogenesis and progression

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