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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI177599

Super-enhancer-driven EFNA1 fuels tumor progression in cervical cancer via the FOSL2-Src/AKT/STAT3 axis

Shu-Qiang Liu,1 Xi-Xi Cheng,1 Shuai He,1 Tao Xia,1 Yi-Qi Li,1 Wan Peng,1 Ya-Qing Zhou,1 Zi-Hao Xu,1 Mi-Si He,2 Yang Liu,1 Pan-Pan Wei,1 Song-Hua Yuan,3 Chang Liu,4 Shu-Lan Sun,4 Dong-Ling Zou,2 Min Zheng,1 Chun-Yan Lan,1 Chun-Ling Luo,1 and Jin-Xin Bei1

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Liu, S. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Cheng, X. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by He, S. in: JCI | PubMed | Google Scholar |

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Xia, T. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Li, Y. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Peng, W. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Zhou, Y. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Xu, Z. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by He, M. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Liu, Y. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Wei, P. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Yuan, S. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Liu, C. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Sun, S. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Zou, D. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Zheng, M. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Lan, C. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Luo, C. in: JCI | PubMed | Google Scholar

1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

2Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China

3Department of Gynecology, The First People's Hospital of Foshan, Foshan, China

4Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China

Find articles by Bei, J. in: JCI | PubMed | Google Scholar |

Published February 18, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI177599.
Copyright © 2025, Liu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 18, 2025 - Version history
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Abstract

Super-enhancers (SEs) are expansive cis-regulatory elements known for amplifying oncogene expression across various cancers. However, their role in cervical cancer (CC), a remarkable global malignancy affecting women, remains underexplored. Here we applied integrated epigenomic and transcriptomic profiling to delineate the distinct SE landscape in CC by analyzing paired tumor and normal tissues. Our study identifies a tumor-specific SE at the EFNA1 locus that drives EFNA1 expression in CC. Mechanically, the EFNA1 SE region contains consensus sequences for the transcription factor FOSL2, whose knockdown markedly suppressed luciferase activity and diminished H3K27ac enrichment within the SE region. Functional analyses further underlined EFNA1’s oncogenic role in CC, linking its overexpression to poor patient outcomes. EFNA1 knockdown strikingly reduced CC cell proliferation, migration, and tumor growth. Moreover, EFNA1 cis-interacted with its receptor EphA2, leading to decreased EphA2 tyrosine phosphorylation and subsequent activation of the Src/AKT/STAT3 forward signaling pathway. Inhibition of this pathway with specific inhibitors substantially attenuated the tumorigenic capacity of EFNA1-overexpressing CC cells in both in vitro and in vivo models. Collectively, our study unveils the critical role of SEs in promoting tumor progression through the FOSL2-EFNA1-EphA2-Src/AKT/STAT3 axis, providing new prognostic and therapeutic avenues for CC patients.

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  • Version 1 (February 18, 2025): In-Press Preview
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