Long noncoding RNA SNHG12 promotes tumour progression and sunitinib resistance by upregulating CDCA3 in renal cell carcinoma

Yuenan Liu; Gong Cheng; Ziwei Huang; Lin Bao; Jingchong Liu; Cheng Wang; Zhiyong Xiong; Lijie Zhou; Tianbo Xu; Di Liu; Hongmei Yang; Ke Chen; Xiaoping Zhang

doi:10.1038/s41419-020-2713-8

Long noncoding RNA SNHG12 promotes tumour progression and sunitinib resistance by upregulating CDCA3 in renal cell carcinoma

Cell Death Dis. 2020 Jul 8;11(7):515. doi: 10.1038/s41419-020-2713-8.

Authors

Yuenan Liu^#¹, Gong Cheng^#¹, Ziwei Huang^#², Lin Bao¹, Jingchong Liu¹, Cheng Wang¹, Zhiyong Xiong¹, Lijie Zhou¹, Tianbo Xu¹, Di Liu¹, Hongmei Yang³, Ke Chen⁴, Xiaoping Zhang⁵

Affiliations

¹ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, 430022, Wuhan, China.
² Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, 430022, Wuhan, China.
³ Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, No. 13 Hangkong Road, 430030, Wuhan, China.
⁴ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, 430022, Wuhan, China. shenke@hust.edu.cn.
⁵ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, 430022, Wuhan, China. xzhang@hust.edu.cn.

^# Contributed equally.

Abstract

Renal cell carcinoma (RCC) is one of the most frequently observed malignant tumours in the urinary system and targeted drug resistance is quite common in RCC. Long noncoding RNA SNHG12 (lncRNA SNHG12) has emerged as a key molecule in numerous human cancers, but its functions in renal cell carcinoma (RCC) sunitinib resistance remain unclear. In this study, we found SNHG12 was highly expressed in RCC tissues and in sunitinib-resistant RCC cells and was associated with a poor clinical prognosis. SNHG12 promoted RCC proliferation, migration, invasion and sunitinib resistance via CDCA3 in vitro. Mechanically, SNHG12 bound to SP1 and prevented the ubiquitylation-dependent proteolysis of SP1. Stabilised SP1 bound to a specific region in the promoter of CDCA3 and increased CDCA3 expression. Furthermore, in vivo experiments showed that SNHG12 increased tumour growth and that knocking down SNHG12 could reverse RCC sunitinib resistance. Our study revealed that the lncRNA SNHG12/SP1/CDCA3 axis promoted RCC progression and sunitinib resistance, which could provide a new therapeutic target for sunitinib-resistant RCC.

Publication types

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

MeSH terms

Animals
Carcinoma, Renal Cell / drug therapy
Carcinoma, Renal Cell / genetics*
Carcinoma, Renal Cell / pathology
Cell Cycle Proteins / genetics
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Disease Progression*
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Kidney Neoplasms / drug therapy
Kidney Neoplasms / genetics*
Kidney Neoplasms / pathology
Male
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Multivariate Analysis
Neoplasm Invasiveness
Prognosis
Protein Binding
Protein Stability
RNA, Long Noncoding / genetics
RNA, Long Noncoding / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Sp1 Transcription Factor / metabolism
Sunitinib / pharmacology
Sunitinib / therapeutic use*
Survival Analysis
Transcription, Genetic
Up-Regulation / drug effects
Up-Regulation / genetics*

Substances

CDCA3 protein, human
Cell Cycle Proteins
RNA, Long Noncoding
RNA, Messenger
SNHG12 long non-coding RNA, human
Sp1 Transcription Factor
Sunitinib