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

Zhen Zhang; Yun-Xin Lu; Fangzhou Liu; Lingjie Sang; Chengyu Shi; Shaofang Xie; Weixiang Bian; Jie-Cheng Yang; Zuozhen Yang; Lei Qu; Shi-Yi Chen; Jun Li; Lu Yang; Qingfeng Yan; Wenqi Wang; Peifen Fu; Jianzhong Shao; Xu Li; Aifu Lin

doi:10.1073/pnas.2206694120

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

Proc Natl Acad Sci U S A. 2023 Feb 21;120(8):e2206694120. doi: 10.1073/pnas.2206694120. Epub 2023 Feb 16.

Authors

Zhen Zhang^{1

2

3}, Yun-Xin Lu⁴, Fangzhou Liu^{1

2

3}, Lingjie Sang¹, Chengyu Shi¹, Shaofang Xie⁵, Weixiang Bian⁵, Jie-Cheng Yang¹, Zuozhen Yang¹, Lei Qu¹, Shi-Yi Chen¹, Jun Li⁶, Lu Yang⁷, Qingfeng Yan¹, Wenqi Wang⁸, Peifen Fu⁹, Jianzhong Shao¹, Xu Li⁵, Aifu Lin^{1

2

3

10

11}

Affiliations

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.

Keywords: Notch signaling; lncRNAs; metastasis; therapeutic target; ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / genetics
Female
Humans
Lung Neoplasms* / genetics
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Receptor, Notch1 / genetics
Receptor, Notch1 / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Ubiquitination

Substances

RNA, Long Noncoding
Ubiquitin-Protein Ligases
Receptor, Notch1
WWP2 protein, human
NOTCH1 protein, human