Teng BW, Zhang KD, Yang YH, Guo ZY, Chen WW, Qiu ZJ. Genome-wide CRISPR-Cas9 screening identifies that hypoxia-inducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis. World J Gastrointest Oncol 2021; 13(11): 1709-1724 [PMID: 34853645 DOI: 10.4251/wjgo.v13.i11.1709]
Corresponding Author of This Article
Zheng-Jun Qiu, MD, Chief Doctor, Director, Surgeon, Shanghai General Hospital of Nanjing Medical University; Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, No. 100 Haining Road, Shanghai 201600, China. qiuzjdoctor@sina.com
Research Domain of This Article
Biochemistry & Molecular Biology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Bu-Wei Teng, Zheng-Jun Qiu, Shanghai General Hospital of Nanjing Medical University, 100 Haining Road, Shanghai 200080, China
Bu-Wei Teng, Lianyungang Clinical College of Nanjing Medical University/The First People’s Hospital of Lianyungang, 6 Zhenhua East Road, Haizhou District, City of Lianyungang, Jiangsu Province 222061, China
Kun-Dong Zhang, Yu-Han Yang, Zeng-Ya Guo, Wei-Wei Chen, Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
Author contributions: Qiu ZJ and Teng BW conceived and supervised the study; Teng BW performed most of the experiments and data analysis; Zhang KD performed most functional experiments and data analysis; Qiu ZJ and Teng BW wrote the manuscript; Yang YH, Guo ZY, and Chen WW took part in the discussions; all the authors discussed the results and commented on the manuscript, and approved the final version.
Supported byNational Natural Science Foundation of China (General Program), No. 81974372 (to Qiu ZJ).
Institutional review board statement: The study was reviewed and approved by the Shanghai General Hospital Institutional Review Board (Approval No. 2020KY083).
Conflict-of-interest statement: The authors declare no conflicts of interest for this work.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zheng-Jun Qiu, MD, Chief Doctor, Director, Surgeon, Shanghai General Hospital of Nanjing Medical University; Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, No. 100 Haining Road, Shanghai 201600, China. qiuzjdoctor@sina.com
Received: April 14, 2021 Peer-review started: April 20, 2021 First decision: June 23, 2021 Revised: June 24, 2021 Accepted: August 23, 2021 Article in press: August 23, 2021 Published online: November 15, 2021
Abstract
BACKGROUND
Pancreatic cancer (PC) is one of the most lethal malignancies worldwide. It is known that the proliferation of PC cells is a critical process in the disease. Previous studies have failed to identify the key genes associated with PC cell proliferation, using bioinformatic analysis, genome-wide association studies, and candidate gene testing.
AIM
To investigate the function of the chromobox 8 (CBX8)/receptor substrate 1 (IRS1)/AKT axis in PC.
METHODS
A genome-wide CRISPR-Cas9 screening was performed to select genes that could facilitate PC cell proliferation. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of CBX8 in PC tissues and cells. The regulatory roles of CBX8 in cell proliferation, migration, and invasion were verified by in vivo and in vitro functional assays.
RESULTS
CBX8 was upregulated in PC tissues and shown to drive PC cell proliferation. Higher expression of CBX8 was correlated with worse outcomes of PC patients from two independent cohorts comprising a total of 116 cases. CBX8 was also proved to serve as a promising therapeutic target for a PC xenograft model. We demonstrated that hypoxia-inducible factor (HIF)-1a induced CBX8 transcription by binding to the promoter of CBX8. CBX8 efficiently activated the PI3K/AKT signaling by upregulating insulin IRS1.
CONCLUSION
CBX8 is a key gene regulated by HIF-1α, and activates the IRS1/AKT pathway, which suggests that targeting CBX8 may be a promising therapeutic strategy for PC.
Core Tip: The authors demonstrated that hypoxia-inducible factor-1a induced chromobox (CBX)8 transcription by binding to the promoter of CBX8. CBX8 efficiently activated the PI3K/AKT signaling by upregulating insulin receptor substrate 1. The newly identified signaling axis may support the development of new therapeutic strategies for pancreatic cancer.
