Interaction between BEND5 and RBPJ suppresses breast cancer growth and metastasis via inhibiting Notch signaling

Abstract

High frequent metastasis is the major cause of breast cancer (BC) mortality among women. However, the molecular mechanisms underlying BC metastasis remain largely unknown. Here, we identified six hub BC metastasis driver genes (BEND5, HSD11B1, NEDD9, SAA2, SH2D2A and TNFSF4) through bioinformatics analysis, among which BEND5 is the most significant gene. Low BEND5 expression predicted advanced stage and shorter overall survival in BC patients. Functional experiments showed that BEND5 could suppress BC growth and metastasis in vitro and in vivo. Mechanistically, BEND5 inhibits Notch signaling via directly interacting with transcription factor RBPJ/CSL. BEN domain of BEND5 interacts with the N-terminal domain (NTD) domain of RBPJ, thus preventing mastermind like transcriptional coactivator (MAML) from forming a transcription activation complex with RBPJ. Our study provides a novel insight into regulatory mechanisms underlying Notch signaling and suggests that BEND5 may become a promising target for BC therapy.

Investigation of the function of the novel tumor marker BEND5 in lung adenocarcinoma based on data mining and in vitro analysis

“…The first study of BEND5 was reported in colorectal cancer and showed the contribution of BEND5 hypermethylation to the proliferation of cells, marking its possibility as a prognostic marker ( 14 ). BEND5 has also been identified as a tumor suppressor gene associated with growth and metastasis in breast cancer ( 15 ). Our bioinformatics analysis showed that BEND5 is expressed at low levels in many cancer types, including colorectal and breast cancer, which is consistent with the findings reported in previous studies.…”

“…To improve the early diagnosis and survival rates of patients with LUAD, specific major molecular pathways and multiple sensitive and reliable biomarkers need to be identified. The relationship between BEND5 and tumor development has been shown in earlier studies (14,15). However, an in-depth description of the role of BEND5 in LUAD is lacking.…”

“…The involvement of BEND proteins in the regulation of gene expression has been observed during early germ cell development, with BEND5 overexpression inducing the differentiation of embryonic stem cells into primordial germ progenitor-like cells in vitro ( 13 ). Deregulation of BEND5 has been reported in malignant tumors, including colorectal cancer ( 14 ) and breast cancer ( 15 ). In colorectal cancer, BEND5 is highly downregulated and exhibits high methylation levels.…”

“…Apoptosis, autophagy, and differentiation are among the key mechanisms via which BEND5 causes a reduction in cell proportions in colorectal cancer, and its reduced expression is correlated with patients’ clinical status and outcome ( 14 ). In breast cancer, Shi et al found that high expression of BEND5 inhibited tumor cell proliferation and metastasis by interacting with the N-terminal domain (NTD) of RBPJ and further inhibiting Notch signaling ( 15 ). The same study also demonstrated that low expression of the BEND5 gene could predict an advanced clinical stage and poor OS outcome in patients with breast cancer ( 15 ).…”

“…In breast cancer, Shi et al found that high expression of BEND5 inhibited tumor cell proliferation and metastasis by interacting with the N-terminal domain (NTD) of RBPJ and further inhibiting Notch signaling ( 15 ). The same study also demonstrated that low expression of the BEND5 gene could predict an advanced clinical stage and poor OS outcome in patients with breast cancer ( 15 ). However, to the best of our knowledge, no report has ever thoroughly investigated the role of BEND5 in LUAD in a comprehensive and integrated manner.…”