ISSN: 1838-7640Theranostics
Global reach, higher impact
Theranostics 2020; 10(19):8903-8923. doi:10.7150/thno.45785 This issue Cite
Research Paper
DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression
1. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
2. Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
3. Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
4. Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
5. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Citation:
Wu JE, Wu YY, Tung CH, Tsai YT, Chen HY, Chen YL, Hong TM. DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. Theranostics 2020; 10(19):8903-8923. doi:10.7150/thno.45785. https://www.thno.org/v10p8903.htm
Other stylesAbstract
The loss of cancer-cell junctions and escape from the primary-tumor microenvironment are hallmarks of metastasis. A tight-junction protein, Claudin 1 (CLDN1), is a metastasis suppressor in lung adenocarcinoma. However, as a metastasis suppressor, the underlying molecular mechanisms of CLDN1 has not been well studied.
Methods: The signaling pathway regulated by CLDN1 was analyzed by Metacore software and validated by immunoblots. The effect of the CLDN1-EPHB6-ERK-SLUG axis on the formation of cancer stem-like cells, drug resistance and metastasis were evaluated by sphere assay, aldefluor assay, flow cytometry, migration assay, cytotoxicity, soft agar assay, immunoprecipitation assay and xenograft experiments. Furthermore, the methylation-specific PCR, pyrosequencing assay, chromatin immunoprecipitation and reporter assay were used to study the epigenetic and RUNX3-mediated CLDN1 transcription. Finally, the molecular signatures of RUNX3/CLDN1/SLUG were used to evaluate the correlation with overall survival by using gene expression omnibus (GEO) data.
Results: We demonstrated that CLDN1 repressed cancer progression via a feedback loop of the CLDN1-EPHB6-ERK1/2-SLUG axis, which repressed metastasis, drug resistance, and cancer stemness, indicating that CLDN1 acts as a metastasis suppressor. CLDN1 upregulated the cellular level of EPHB6 and enhanced its activation, resulting in suppression of ERK1/2 signaling. Interestingly, DNA hypermethylation of the CLDN1 promoter abrogated SLUG-mediated suppression of CLDN1 in low-metastatic cancer cells. In contrast, the histone deacetylase inhibitor trichostatin A or vorinostat facilitated CLDN1 expression in high-metastatic cancer cells and thus increased the efficacy of chemotherapy. Combined treatment with cisplatin and trichostatin A or vorinostat had a synergistic effect on cancer-cell death.
Conclusions: This study revealed that DNA methylation maintains CLDN1 expression and then represses lung cancer progression via the CLDN1-EPHB6-ERK1/2-SLUG axis. Because CLDN1 enhances the efficacy of chemotherapy, CLDN1 is not only a prognostic marker but a predictive marker for lung adenocarcinoma patients who are good candidates for chemotherapy. Forced CLDN1 expression in low CLDN1-expressing lung adenocarcinoma will increase the chemotherapy response, providing a novel therapeutic strategy.
Keywords: DNA methylation, CLDN1, cancer stem-like cells, drug resistance, metastasis.
Citation styles
APA
Wu, J.E., Wu, Y.Y., Tung, C.H., Tsai, Y.T., Chen, H.Y., Chen, Y.L., Hong, T.M. (2020). DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. Theranostics, 10(19), 8903-8923. https://doi.org/10.7150/thno.45785.
ACS
Wu, J.E.; Wu, Y.Y.; Tung, C.H.; Tsai, Y.T.; Chen, H.Y.; Chen, Y.L.; Hong, T.M. DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. Theranostics 2020, 10 (19), 8903-8923. DOI: 10.7150/thno.45785.
NLM
Wu JE, Wu YY, Tung CH, Tsai YT, Chen HY, Chen YL, Hong TM. DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. Theranostics 2020; 10(19):8903-8923. doi:10.7150/thno.45785. https://www.thno.org/v10p8903.htm
CSE
Wu JE, Wu YY, Tung CH, Tsai YT, Chen HY, Chen YL, Hong TM. 2020. DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. Theranostics. 10(19):8903-8923.
This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.