Abstract
Deregulation of the basic helix‐loop‐helix family member e41 (BHLHE41) has been characterized as a marker of progression of several cancers. In this study, we aimed to explore the mechanism by which BHLHE41 regulates the invasion of breast cancer cells. BHLHE41 suppresses, whereas the silencing of BHLHE41 promotes tumour invasion of both MCF‐7 and MDA‐MB‐231 cells. Meanwhile, BHLHE41 down‐regulated the transcription and translation of SNAI1, SNAI2, VIM and CDH2, and up‐regulated those of CLDN1, CLDN4 and CDH1. Reporter assay indicated that silencing of BHLHE41 dramatically activated the MAPK/JNK signalling pathway in MCF‐7 cell line and the hypoxia signalling pathway in MDA‐MB‐231 cell line. Furthermore, silencing of BHLHE41 activated the MAPK/JNK signalling pathway by up‐regulating phosphorylated JNK and failed to affect the expression of HIF‐1 alpha in MCF‐7 cells. After blocking the MAPK/JNK signalling pathway by specific inhibitor SP600125, silencing of BHLHE41 failed to promote tumour cell invasion. These results suggest that BHLHE41 facilitates MCF‐7 cell invasion mainly via the activation of MAPK/JNK signalling pathway. In conclusion, although BHLHE41 suppresses tumour invasion in MCF‐7 and MDA‐MB‐231 cell lines, the specific regulatory mechanisms may be different.
Highlights
Basic helix-loop-helix family member e41 (BHLHE41, known as SHARP1, DEC2 and BHLHB3) is mapped to human chromosome 12p12.1
We previously reported that BHLHE40, another member of the DEC subfamily, regulated MCF-7 cell invasion through interaction with SP1 and negatively regulated the transcription of CLDN1
A few recent studies have shown that BHLHE40 and basic helix-loop-helix family member e41 (BHLHE41) are involved in regulating cell invasion and metastasis.[5,6,19,24-27]
Summary
Basic helix-loop-helix family member e41 (BHLHE41, known as SHARP1, DEC2 and BHLHB3) is mapped to human chromosome 12p12.1. BHLHE41 was demonstrated to be a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer and suppressed metastasis by promoting the degradation of hypoxia-inducible factors in MDA-MB-231 cells.[8]. Montagner et al[8] demonstrated that BHLHE41 suppressed invasion and metastasis by promoting the degradation of HIF-1α in triple-negative breast cancer cell line MDA-MB-231. They pointed out that BHLHE41 expression correlated with the higher metastatic molecular phenotype (triple-negative breast cancer). After blocking MAPK-JNK signalling pathway by an inhibitor, we found that BHLHE41 silencing by siRNA failed to promote tumour cell invasion. In contrast to that in the MDA-MB-231 cell line, BHLHE41 suppressed invasion via MAPK/JNK signalling pathway in MCF-7 cell line
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