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

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.

Construction of a PANoptosis-Related LncRNA Prognostic Model and Study on the Function of Linc01135 for Gastric Cancer

“…Utilizing CTG, colony formation assays, and scratch assays, we observed that Linc01135 enhances the proliferative and migratory capabilities of gastric cancer cells. Furthermore, numerous studies have argued that that long noncoding RNAs (lncRNAs) associate with protein partners exerting an important impact in cancer [49][50][51][52]. Therefore, we operate RNA Pulldown and RIP experiments confirmed the specific binding between Linc01135 and CDC45 while FISH combined with immunofluorescence demonstrated their co-localization within the cell nucleus.…”

Myofibrillogenesis Regulator‐1 Regulates the Ubiquitin Lysosomal Pathway of Notch3 Intracellular Domain Through E3 Ubiquitin‐Protein Ligase Itchy Homolog in the Metastasis of Non‐Small Cell Lung Cancer

“…The classic lysosomal pathway is often associated with autophagy and apoptosis, but in stable MR‐1‐ knockdown H1299 cells, it did not cause the changes of autophagy markers (p62) and apoptosis markers (PARP and caspase3) through Western blot. The degradation mode of NICD3 is different from that of NICD1 and NICD2, [ 44 , 45 , 46 ] which may be related to the number and position of lysine residues in the NICD3 sequence. [ 47 ] We conducted sequence alignment of NICD1‐3 through Cluster X2.1, which was visualized by GeneDoc, and found that only 21 lysine residues were present in the NICD3 sequence, and compared to NICD1 and 2, there were no lysine dense regions (Figure S7 , Supporting Information, 400–450).…”

Fibroblasts: invigorated targets in pre-metastatic niche formation

“…LncRNA, with a length exceeding 200 nucleotides, is regarded as a type of RNA that cannot encode and translate into proteins and exerts a variety of functions on regulating lung metastasis of breast cancer 87 . It has been well documented that lncRNA BREA2 is able to suppress the formation of WWP2-NICD1 complex, thereby stabilizing NICD1 to strengthen the transduction of Notch signals and further accelerate the lung metastasis of breast cancer 88 . In addition, the overexpression of lncRNA ROR in the epithelial cells of breast cancer is prone to orchestrate the process of EMT through repressing the degradation of miR-205 target genes, which paves the way for exacerbating the lung metastasis of breast cancer.…”