Volume 32, No 4, Apr 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 4, April 2022: 359-374

ORIGINAL ARTICLES

EGFR signaling promotes nuclear translocation of plasma membrane protein TSPAN8 to enhance tumor progression via STAT3-mediated transcription

Xiaoqing Lu^1,2,† , Liwei An^3,† , Guangjian Fan^1,4,† , Lijuan Zang^5,† , Weiyi Huang¹ , Junjian Li¹ , Jun Liu¹ , Weiyu Ge¹ , Yuwei Huang⁶ , Jingxuan Xu¹ , Shaoqian Du¹ , Yuan Cao¹ , Tianhao Zhou¹ , Huijing Yin¹ , Li Yu⁶ , Shi Jiao⁷ , Hongxia Wang^1,*

¹State Key Laboratory of Oncogenes and Related Genes, Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
²Department of Breast Surgery, Shanxi Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, Shanxi, China
³Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, School of Medicine, Tongji University, Shanghai, China
⁴Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁵Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁶State Key Laboratory of Membrane Biology, Tsinghua-Peking University Joint Center for Life Sciences, School of Life Science, Tsinghua University, Beijing, China
⁷State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
^†These authors contributed equally: Xiaoqing Lu, Liwei An, Guangjian Fan, Lijuan Zang
Correspondence: Hongxia Wang(whx365@126.com)

TSPAN family of proteins are generally considered to assemble as multimeric complexes on the plasma membrane. Our previous work uncovered that TSPAN8 can translocate into the nucleus as a membrane-free form, a process that requires TSPAN8 palmitoylation and association with cholesterol to promote its extraction from the plasma membrane and subsequent binding with 14-3-3θ and importin-β. However, what upstream signal(s) regulate(s) the nuclear translocation of TSPAN8, the potential function of TSPAN8 in the nucleus, and the underlying molecular mechanisms all remain unclear. Here, we demonstrate that, epidermal growth factor receptor (EGFR) signaling induces TSPAN8 nuclear translocation by activating the kinase AKT, which in turn directly phosphorylates TSPAN8 at Ser129, an event essential for its binding with 14-3-3θ and importin ß1. In the nucleus, phosphorylated TSPAN8 interacts with STAT3 to enhance its chromatin occupancy and therefore regulates transcription of downstream cancer-promoting genes, such as MYC, BCL2, MMP9, etc. The EGFR–AKT–TSPAN8–STAT3 axis was found to be hyperactivated in multiple human cancers, and associated with aggressive phenotype and dismal prognosis. We further developed a humanized monoclonal antibody hT8Ab4 that specifically recognizes the large extracellular loop of TSPAN8 (TSPAN8-LEL), thus being able to block the extraction of TSPAN8 from the plasma membrane and consequently its nuclear localization. Importantly, both in vitro and in vivo studies demonstrated an antitumor effect of hT8Ab4. Collectively, we discovered an unconventional function of TSPAN8 and dissected the underlying molecular mechanisms, which not only showcase a new layer of biological complexity of traditional membrane proteins, but also shed light on TSPAN8 as a novel therapeutic target for refractory cancers.

https://doi.org/10.1038/s41422-022-00628-8

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