Jingshu Liu1,2,3,4, Jiangfeng Qiu5, Zhiqi Zhang6, Lei Zhou7,8,9, Yunzhe Li1,2, Dongyan Ding1,2, Yang Zhang10, Dongling Zou2, Dong Wang2, Qi Zhou11,12,13,14, Tingyuan Lang15,16,17,18. 1. College of Bioengineering, Chongqing University, 400044, Chongqing, People's Republic of China. 2. Department of Gynecologic Oncology, Chongqing University Cancer Hospital, 400030, Chongqing, People's Republic of China. 3. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, 400030, Chongqing, People's Republic of China. 4. Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, 400044, Chongqing, People's Republic of China. 5. Department of Gastrointestinal Surgery, Renji Hospital Shanghai Jiao Tong University School of Medicine, 200127, Shanghai, People's Republic of China. 6. Department of General Surgery, School of Medicine, Shanghai Fourth People's Hospital Affiliated to Tongji University, 200081, Shanghai, People's Republic of China. 7. Singapore Eye Research Institute, The academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore, Singapore. 8. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 9. Ophthalmology and Visual Sciences Academic Clinical Research Program, Duke-NUS Medical School, National University of Singapore, Singapore, Singapore. 10. Laboratory Department, Chongqing University Cancer Hospital, 400030, Chongqing, People's Republic of China. 11. College of Bioengineering, Chongqing University, 400044, Chongqing, People's Republic of China. cqzl_zq@163.com. 12. Department of Gynecologic Oncology, Chongqing University Cancer Hospital, 400030, Chongqing, People's Republic of China. cqzl_zq@163.com. 13. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, 400030, Chongqing, People's Republic of China. cqzl_zq@163.com. 14. Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, 400044, Chongqing, People's Republic of China. cqzl_zq@163.com. 15. College of Bioengineering, Chongqing University, 400044, Chongqing, People's Republic of China. michaellang2009@163.com. 16. Department of Gynecologic Oncology, Chongqing University Cancer Hospital, 400030, Chongqing, People's Republic of China. michaellang2009@163.com. 17. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, 400030, Chongqing, People's Republic of China. michaellang2009@163.com. 18. Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, 400044, Chongqing, People's Republic of China. michaellang2009@163.com.
Abstract
BACKGROUND: Cancer stem cells (CSCs) are the root of human cancer development and the major cause of treatment failure. Aberrant elevation of SOX4, a member of SOX (SRY-related HMG-box) family transcription factors, has been identified in many types of human cancer and promotes cancer development. However, the role of SOX4 in CSCs, especially at a proteome-wide level, has remained elusive. The aim of this study is to investigate the effect of SOX4 on the stemness of CSCs and reveal the underlying mechanisms by identification of SOX4-induced proteome changes through proteomics study. RESULTS: Overexpression of SOX4 promotes sphere formation and self-renewal of colorectal cancer cells in vitro and in vivo and elevates the expression levels of CSCs markers. Through iTRAQ-based quantitative proteomics analysis, 215 differentially expressed proteins (128 upregulated, 87 downregulated) in SOX4-overexpressing HCT-116 spheres were identified. The bioinformatic analysis highlighted the importance of HDAC1 as the fundamental roles of its impacted pathways in stem cell maintenance, including Wnt, Notch, cell cycle, and transcriptional misregulation in cancer. The mechanistic study showed that SOX4 directly binds to the promoter of HDAC1, promotes HDAC1 transcription, thereby supporting the stemness of colorectal cancer cells. HDAC1 hallmarks colorectal cancer stem cells and depletion of HDAC1 abolished the stimulatory effect of SOX4. Furthermore, SOX4-HDAC1 axis is conserved in multiple types of cancer. CONCLUSIONS: The results of this study reveal SOX4-induced proteome changes in HCT-116 spheres and demonstrates that transcriptional activation of HDAC1 is the primary mechanism underlying SOX4 maintaining CSCs. This finding suggests that HDAC1 is a potential drug target for eradicating SOX4-driven human CSCs.
BACKGROUND:Cancer stem cells (CSCs) are the root of humancancer development and the major cause of treatment failure. Aberrant elevation of SOX4, a member of SOX (SRY-related HMG-box) family transcription factors, has been identified in many types of humancancer and promotes cancer development. However, the role of SOX4 in CSCs, especially at a proteome-wide level, has remained elusive. The aim of this study is to investigate the effect of SOX4 on the stemness of CSCs and reveal the underlying mechanisms by identification of SOX4-induced proteome changes through proteomics study. RESULTS: Overexpression of SOX4 promotes sphere formation and self-renewal of colorectal cancer cells in vitro and in vivo and elevates the expression levels of CSCs markers. Through iTRAQ-based quantitative proteomics analysis, 215 differentially expressed proteins (128 upregulated, 87 downregulated) in SOX4-overexpressing HCT-116 spheres were identified. The bioinformatic analysis highlighted the importance of HDAC1 as the fundamental roles of its impacted pathways in stem cell maintenance, including Wnt, Notch, cell cycle, and transcriptional misregulation in cancer. The mechanistic study showed that SOX4 directly binds to the promoter of HDAC1, promotes HDAC1 transcription, thereby supporting the stemness of colorectal cancer cells. HDAC1 hallmarks colorectal cancer stem cells and depletion of HDAC1 abolished the stimulatory effect of SOX4. Furthermore, SOX4-HDAC1 axis is conserved in multiple types of cancer. CONCLUSIONS: The results of this study reveal SOX4-induced proteome changes in HCT-116 spheres and demonstrates that transcriptional activation of HDAC1 is the primary mechanism underlying SOX4 maintaining CSCs. This finding suggests that HDAC1is a potential drug target for eradicating SOX4-driven human CSCs.
Authors: Sandra D Castillo; Ander Matheu; Niccolo Mariani; Julian Carretero; Fernando Lopez-Rios; Robin Lovell-Badge; Montse Sanchez-Cespedes Journal: Cancer Res Date: 2011-11-14 Impact factor: 12.701
Authors: Gaurav A Mehta; Joel S Parker; Grace O Silva; Katherine A Hoadley; Charles M Perou; Michael L Gatza Journal: Breast Cancer Res Treat Date: 2017-02-07 Impact factor: 4.872
Authors: Birdal Bilir; Adeboye O Osunkoya; W Guy Wiles; Soma Sannigrahi; Veronique Lefebvre; Daniel Metzger; Demetri D Spyropoulos; W David Martin; Carlos S Moreno Journal: Cancer Res Date: 2015-12-23 Impact factor: 12.701
Authors: Pedro P Medina; Sandra D Castillo; Sandra Blanco; Marta Sanz-Garcia; Cristina Largo; Sara Alvarez; Jun Yokota; Ana Gonzalez-Neira; Javier Benitez; Hans C Clevers; Juan C Cigudosa; Pedro A Lazo; Montse Sanchez-Cespedes Journal: Hum Mol Genet Date: 2009-01-19 Impact factor: 6.150