Abstract
Cadherin 11 (CDH11) expression is detected only in invasive breast cancer cells and aggressive breast cancer specimens. However, little is known about the molecular mechanisms of CDH11 transcriptional regulation. Here, we report that interleukin enhancer binding factor 3 (ILF3) interacts with Homeobox C8 (HOXC8) to activate CDH11 transcription in breast cancer cells. Using co-immunoprecipitation and mass spectrometry analyses, ILF3 is shown to interact with HOXC8 in breast cancer cells. We demonstrate that ILF3 binds to the CDH11 promoter on nucleotides –2982 ~ –2978 and –2602 ~ 2598 and interacts with HOXC8 to co-activate CDH11 transcription. We further show that ILF3 promotes proliferation and migration, at least partially, by facilitating CDH11 expression in breast cancer cells. Moreover, immunohistochemistry (IHC) shows that expression of CDH11, ILF3 and HOXC8 are all upregulated in breast cancer specimens compared to normal breast tissues. Importantly, the expression levels of CDH11, ILF3 and HOXC8 are elevated in the advanced stages of breast cancer, and high expression of CDH11, ILF3 and HOXC8 is associated with poor distant metastasis-free survival (DMFS) for breast cancer patients.
Highlights
The cadherin switch, which is an increase in the expression of N-cadherin and/or cadherin 11 and a decrease in E-cadherin, is associated with both the epithelial-to-mesenchymal transition (EMT) and cancer progression [1, 2]
We found that Homeobox C8 (HOXC8) bound to Cadherin 11 (CDH11) promoter to activate CDH11 transcription
Combination analyses of CDH11, interleukin enhancer binding factor 3 (ILF3) and HOXC8 using Kaplan-Meier plotter further showed a poor association for distant metastasis-free survival (P = 0.0057) (Supplementary Figure 5). These results indicated that CDH11, ILF3 and HOXC8 were highly upregulated in the advanced stages of breast cancer, and high expression of CDH11, ILF3 and HOXC8 were associated with a poor DMSF for breast cancer patients
Summary
The cadherin switch, which is an increase in the expression of N-cadherin and/or cadherin 11 and a decrease in E-cadherin, is associated with both the epithelial-to-mesenchymal transition (EMT) and cancer progression [1, 2]. We previously reported that Homeobox C8 (HOXC8) acts as a transcription factor to induce CDH11 expression in breast cancer cells [11, 13]. HOXC8 belongs to the 39-member Homeobox (HOX) family and participates in multiple physiological processes, such as cell proliferation, migration, adhesion, and differentiation [14]. All HOX (homeobox) genes encode homeodomain-containing transcription factors and associate with other protein factors to regulate the expression of multiple genes [18, 19]. To further clarify the roles of HOXC8 in regulation of CDH11 transcription in breast cancer cells, we immunoprecipitated HOXC8 protein complexes and observed that interleukin enhancerbinding factor 3 (ILF3) co-precipitated with the HOXC8 protein in this study
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