2. Academic Validation
  3. Activating STING/TBK1 suppresses tumor growth via degrading HPV16/18 E7 oncoproteins in cervical cancer

Activating STING/TBK1 suppresses tumor growth via degrading HPV16/18 E7 oncoproteins in cervical cancer

  • Cell Death Differ. 2023 Nov 25. doi: 10.1038/s41418-023-01242-w.
Xiaodan Huang # 1 2,  Lanqing Huo # 1 2,  Beibei Xiao # 1,  Yi Ouyang # 1 2,  Foping Chen 1 2,  Junyun Li 1 2,  Xueping Zheng 1,  Denghui Wei 1,  Yuanzhong Wu 1,  Ruhua Zhang 1,  Xinping Cao 3 4,  Tiebang Kang 5,  Ying Gao 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.
  • 2 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.
  • 3 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China. caoxp@sysucc.org.cn.
  • 4 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China. caoxp@sysucc.org.cn.
  • 5 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China. kangtb@sysucc.org.cn.
  • 6 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China. gaoying@sysucc.org.cn.
  • # Contributed equally.
PMID: 38007552 DOI: 10.1038/s41418-023-01242-w
Abstract

Cervical Cancer is the most common gynecologic Cancer, etiologically related to persistent Infection of human papillomavirus (HPV). Both the host innate immunity system and the invading HPV have developed sophisticated and effective mechanisms to counteract each other. As a central innate immune sensing signaling adaptor, stimulator of interferon genes (STING) plays a pivotal role in Antiviral and antitumor immunity, while viral oncoproteins E7, especially from HPV16/18, are responsible for cell proliferation in cervical Cancer, and can inhibit the activity of STING as reported. In this report, we find that activation of STING-TBK1 (TANK-binding kinase 1) promotes the ubiquitin-proteasome degradation of E7 oncoproteins to suppress cervical Cancer growth. Mechanistically, TBK1 is able to phosphorylate HPV16/18 E7 oncoproteins at Ser71/Ser78, promoting the ubiquitination and degradation of E7 oncoproteins by E3 Ligase HUWE1. Functionally, activated STING inhibits cervical Cancer cell proliferation via down-regulating E7 oncoproteins in a TBK1-dependent manner and potentially synergizes with radiation to achieve better effects for antitumor. Furthermore, either genetically or pharmacologically activation of STING-TBK1 suppresses cervical Cancer growth in mice, which is independent on its innate immune defense. In conclusion, our findings represent a new layer of the host innate immune defense against oncovirus and provide that activating STING/TBK1 could be a promising strategy to treat patients with HPV-positive cervical Cancer.

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