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超级增强子驱动的 SOX2 通过染色质重排促进鼻咽癌的肿瘤形成。

Super-enhancer driven SOX2 promotes tumor formation by chromatin re-organization in nasopharyngeal carcinoma.

机构信息

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.

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.

出版信息

EBioMedicine. 2023 Dec;98:104870. doi: 10.1016/j.ebiom.2023.104870. Epub 2023 Nov 14.

DOI:10.1016/j.ebiom.2023.104870

PMID:37967508

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10679863/

Abstract

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.

摘要

背景

鼻咽癌（NPC）是一种恶性头颈部癌症，在中国南方和东南亚地区发病率较高。有远处转移和复发性 NPC 的患者预后较差。因此，更好地了解 NPC 的发病机制可能会发现新的治疗方法来满足未满足的临床需求。

方法

使用 H3K27ac ChIP-seq 和 HiChIP 来了解增强子景观和染色体相互作用。进行全基因组测序以分析基因组变异与表观遗传失调之间的关系。使用 CRISPRi 和 JQ1 处理来评估 SOX2 SE 的转录调控。进行集落形成测定、生存分析和体内皮下患者来源的异种移植测定，以研究 SOX2 在 NPC 中的功能和临床相关性。

发现

我们全局绘制了增强子景观，并生成了 NPC 增强子连接组，将 NPC 特异性增强子和 SEs 联系起来。我们在受超级增强子调控的基因、生存相关基因和 NPC 必需基因中发现了五个重叠基因，包括 SOX2。当应用靶向不同 SOX2 SE 的 CRISPRi 或 JQ1 处理时，SOX2 的 mRNA 表达受到抑制。接下来，我们在 SOX2 SE 中发现了一个遗传变异（Chr3:181422197，G > A），该变异与 SOX2 的高表达和不良预后相关。此外，SOX2 在 NPC 中高表达，并与 NPC 患者的短生存期相关。SOX2 的敲低抑制了体外和体内的肿瘤生长。