BHLHE41 suppresses MCF‐7 cell invasion via MAPK/JNK pathway

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.

[1]  Y. Muragaki,et al.  Smad3 Suppresses Epithelial Cell Migration and Proliferation via the Clock Gene Dec1, Which Negatively Regulates the Expression of Clock Genes Dec2 and Per1. , 2019, The American journal of pathology.

[2]  Jun Lu,et al.  Overexpression of BHLHE41, correlated with DNA hypomethylation in 3′UTR region, promotes the growth of human clear cell renal cell carcinoma , 2019, Oncology reports.

[3]  Takahito Otani,et al.  Anisomycin, a JNK and p38 activator, suppresses cell–cell junction formation in 2D cultures of K38 mouse keratinocyte cells and reduces claudin-7 expression, with an increase of paracellular permeability in 3D cultures , 2018, Histochemistry and Cell Biology.

[4]  Baolan Lu,et al.  MicroRNA-873 acts as a tumor suppressor in esophageal cancer by inhibiting differentiated embryonic chondrocyte expressed gene 2. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[5]  Liang Wang,et al.  Interaction with SP1, but not binding to the E‐box motifs, is responsible for BHLHE40/DEC1‐induced transcriptional suppression of CLDN1 and cell invasion in MCF‐7 cells , 2018, Molecular carcinogenesis.

[6]  H. Kijima,et al.  Correlation between DEC1/DEC2 and epithelial-mesenchymal transition in human prostate cancer PC-3 cells , 2018, Molecular medicine reports.

[7]  L. Qi,et al.  Loss of the basic helix-loop-helix transcription factor Bhlhe41 induces cell death and impairs neurite outgrowth in Neuro2a cells , 2018, Molecular and Cellular Biochemistry.

[8]  Ying-Hui Fu,et al.  DEC2 modulates orexin expression and regulates sleep , 2018, Proceedings of the National Academy of Sciences.

[9]  P. Ratcliffe,et al.  Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway , 2017, PLoS genetics.

[10]  Liang Zhao,et al.  LASP2 suppresses colorectal cancer progression through JNK/p38 MAPK pathway meditated epithelial-mesenchymal transition , 2017, Cell Communication and Signaling.

[11]  Y. Kato,et al.  DEC2 expression antagonizes cisplatin-induced apoptosis in human esophageal squamous cell carcinoma , 2017, Molecular medicine reports.

[12]  Byoungduck Park,et al.  Suppression of Hepatic Epithelial-to-Mesenchymal Transition by Melittin via Blocking of TGFβ/Smad and MAPK-JNK Signaling Pathways , 2017, Toxins.

[13]  Markus Jaritz,et al.  Essential role of the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells , 2017, Nature Immunology.

[14]  M. Maishan,et al.  Tumor Necrosis Factor‐α Increases Claudin‐1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes , 2017, Journal of cellular physiology.

[15]  Shuai Zong,et al.  DEC2 suppresses tumor proliferation and metastasis by regulating ERK/NF-κB pathway in gastric cancer. , 2016, American journal of cancer research.

[16]  S. Chanock,et al.  Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41 , 2016, Nature Communications.

[17]  Jian Tang,et al.  Roles of SHARP1 in thyroid cancer. , 2016, Molecular medicine reports.

[18]  Jianshu Lu,et al.  MicroRNA-138 functions as a tumor suppressor in osteosarcoma by targeting differentiated embryonic chondrocyte gene 2 , 2016, Journal of Experimental & Clinical Cancer Research.

[19]  Y. Muragaki,et al.  DEC1 and DEC2 Crosstalk between Circadian Rhythm and Tumor Progression , 2016, Journal of Cancer.

[20]  H. Yagi,et al.  Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells , 2015, Molecular and Cellular Biology.

[21]  T. Kawamoto,et al.  Involvement of c-Myc in the proliferation of MCF-7 human breast cancer cells induced by bHLH transcription factor DEC2. , 2015, International journal of molecular medicine.

[22]  X. Wan,et al.  Suppression of the epithelial-mesenchymal transition by SHARP1 is linked to the NOTCH1 signaling pathway in metastasis of endometrial cancer , 2014, BMC Cancer.

[23]  Ying-Hui Fu,et al.  Sick and tired: how molecular regulators of human sleep schedules and duration impact immune function , 2013, Current Opinion in Neurobiology.

[24]  Liang Wang,et al.  DEC1 is positively associated with the malignant phenotype of invasive breast cancers and negatively correlated with the expression of claudin-1. , 2013, International journal of molecular medicine.

[25]  T. Kawamoto,et al.  The BHLH transcription factor DEC1 plays an important role in the epithelial-mesenchymal transition of pancreatic cancer. , 2012, International journal of oncology.

[26]  S. Bicciato,et al.  SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors , 2012, Nature.

[27]  T. Kawamoto,et al.  Basic helix‐loop‐helix transcription factor DEC1 negatively regulates cyclin D1 , 2011, The Journal of pathology.

[28]  T. Kawamoto,et al.  Anti‐apoptotic effect of the basic helix‐loop‐helix (bHLH) transcription factor DEC2 in human breast cancer cells , 2010, Genes to cells : devoted to molecular & cellular mechanisms.

[29]  Seiji Nishino,et al.  The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals , 2009, Science.

[30]  M. Campiglio,et al.  BHLHB3: a candidate tumor suppressor in lung cancer , 2008, Oncogene.

[31]  Y. Wan,et al.  DEC1 Negatively Regulates the Expression of DEC2 through Binding to the E-box in the Proximal Promoter* , 2003, The Journal of Biological Chemistry.

[32]  T. Kawamoto,et al.  Dec1 and Dec2 are regulators of the mammalian molecular clock , 2002, Nature.

[33]  Horst Hameister,et al.  SHARP is a novel component of the Notch/RBP‐Jκ signalling pathway , 2002 .

[34]  Jian Tang,et al.  Roles of SHARP 1 in thyroid cancer , 2016 .

[35]  R. Stam,et al.  Unique BHLHB3 overexpression in pediatric acute myeloid leukemia with t(6;11)(q27;q23) , 2014, Leukemia.