LncRNA Promotes Metastasis by Disrupting the WWP2-mediated Ubiquitination of Notch1

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2023 Feb 16

PMID 36795754

Authors

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

Affiliations

Soon will be listed here.

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) 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, impairs WWP2-NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. 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 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.

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