Super-enhancer driven SOX2 promotes tumor formation by chromatin re-organization in nasopharyngeal carcinomaResearch in context
Shang-Xin Liu,
Chong Wang,
Ruo-Bin Lin,
Wei-Yue Ding,
Gaurab Roy,
Hong-Bo Wang,
Ting Yang,
Qian Liu,
Yi-Ling Luo,
Shui-Lin Jin,
Mu-Sheng Zeng,
Bo Zhao,
Qian Zhong
Affiliations
Shang-Xin Liu
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
Chong Wang
Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA; Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA
Ruo-Bin Lin
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
Wei-Yue Ding
School of Mathematics, Harbin Institute of Technology, Harbin, PR China
Gaurab Roy
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
Hong-Bo Wang
Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
Ting Yang
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
Qian Liu
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; Department of Ultrasound Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
Yi-Ling Luo
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
Shui-Lin Jin
School of Mathematics, Harbin Institute of Technology, Harbin, PR China
Mu-Sheng Zeng
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Guangzhou, PR China; Corresponding author. No. 651, Dongfeng East Road, Guangzhou, Guangdong Province, PR China.
Bo Zhao
Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA; Corresponding author. No. 181, Longwood Avenue, Boston, MA 02115, USA.
Qian Zhong
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China; Corresponding author. No. 651, Dongfeng East Road, Guangzhou, Guangdong Province, PR China.
Summary: Background: Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with a high incidence in Southern China and Southeast Asia. Patients with remote metastasis and recurrent NPC have poor prognosis. Thus, a better understanding of NPC pathogenesis may identify novel therapies to address the unmet clinical needs. Methods: H3K27ac ChIP-seq and HiChIP was applied to understand the enhancer landscapes and the chromosome interactions. Whole genome sequencing was conducted to analyze the relationship between genomic variations and epigenetic dysregulation. CRISPRi and JQ1 treatment were used to evaluate the transcriptional regulation of SOX2 SEs. Colony formation assay, survival analysis and in vivo subcutaneous patient-derived xenograft assays were applied to explore the function and clinical relevance of SOX2 in NPC. Findings: We globally mapped the enhancer landscapes and generated NPC enhancer connectomes, linking NPC specific enhancers and SEs. We found five overlapped genes, including SOX2, among super-enhancer regulated genes, survival related genes and NPC essential genes. The mRNA expression of SOX2 was repressed when applying CRISPRi targeting different SOX2 SEs or JQ1 treatment. Next, we identified a genetic variation (Chr3:181422197, G > A) in SOX2 SE which is correlated with higher expression of SOX2 and poor survival. In addition, SOX2 was highly expressed in NPC and is correlated with short survival in patients with NPC. Knock-down of SOX2 suppressed tumor growth in vitro and in vivo. Interpretation: Our study demonstrated the super-enhancer landscape with chromosome interactions and identified super-enhancer driven SOX2 promotes tumorigenesis, suggesting that SOX2 is a potential therapeutic target for patients with NPC. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
