lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1

Author:

Zhang Zhen123,Lu Yun-xin4,Liu Fangzhou123,Sang Lingjie1,Shi Chengyu1ORCID,Xie Shaofang5,Bian Weixiang5,Yang Jie-cheng1,Yang Zuozhen1,Qu Lei1,Chen Shi-yi1,Li Jun6,Yang Lu7,Yan Qingfeng1,Wang Wenqi8ORCID,Fu Peifen9,Shao Jianzhong1,Li Xu5ORCID,Lin Aifu1231011

Affiliation:

1. MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China

2. Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China

3. Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang 310058, China

4. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, China

5. Key Laboratory of Structural Biology of Zhejiang Province, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, Zhejiang 310024, China

6. Department of Pathology School of Medicine, The First Affiliated Hospital Zhejiang University, Hangzhou, Zhejiang 310003, China

7. Department of Radiotherapy, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine South China University of Technology, Guangzhou 510080, China

8. Department of Developmental and Cell Biology, University of California, Irvine, CA 92697

9. Department of Breast Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China

10. Breast Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China

11. International School of Medicine, International Institutes of Medicine, The 4th Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China

Abstract

Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2–NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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