TY - JOUR
T1 - Transcriptional repressor Kaiso promotes epithelial to mesenchymal transition and metastasis in prostate cancer through direct regulation of miR-200c
AU - Abisoye-Ogunniyan, Abisola
AU - Lin, Huxian
AU - Ghebremedhin, Anghesom
AU - Salam, Ahmad Bin
AU - Karanam, Balasubramanyam
AU - Theodore, Shaniece
AU - Jones-Trich, Jacqueline
AU - Davis, Melissa B
AU - Grizzle, William
AU - Wang, Honghe
AU - Yates, Clayton
N1 - Funding Information:
This work was supported by grants U54MD007585 , ( NIH/RCMI ) [CY], U54CA118623-01 ( NIH/NCI ) [CY], ( NIH/NCI ) 1 R21 CA188799-01 [CY]; and a Department of Defense Grant , PC120913 , W81XWH-10-1-0543 . Statistical analysis was performed by the University Alabama at Birmingham and Tuskegee University Statistical Cores. We also thank members of the Yates laboratory and the Davis laboratory for their technical assistance, comments and discussions.
Funding Information:
This work was supported by grants U54MD007585, (NIH/RCMI) [CY], U54CA118623-01 (NIH/NCI) [CY], (NIH/NCI) 1 R21 CA188799-01 [CY]; and a Department of Defense Grant, PC120913, W81XWH-10-1-0543. Statistical analysis was performed by the University Alabama at Birmingham and Tuskegee University Statistical Cores. We also thank members of the Yates laboratory and the Davis laboratory for their technical assistance, comments and discussions.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - The loss of miR-200 family, through DNA methylation, results in cancer cells undergoing an epithelial to mesenchymal transition (EMT), and metastasis. In this study, we established that the transcriptional repressor Kaiso directly binds methylated regions of the miR-200 family, and this is reversed with 5-aza treatment. sh-Kaiso PC-3 cells display increased miR-200-a/b/c, miR-141, and miR-429 expression, with miR-200c demonstrating the most significant increase. Interestingly, overexpression of EGFR or treatment with EGF decreases miR-200c expression and this is reversed after treatment with EGFR specific kinase inhibitor PD153035. However, EGF did not have a significant effect on miR-200c in sh-Kaiso DU-145 or PC-3 cell lines, suggesting Kaiso silences miR-200c through the activation of EGFR signaling. Overexpression of Kaiso in LNCaP cells results in decreased expression of miR-200-a/b/c, miR-141, and miR-429, along with increased expression of ZEB1, p-EGFR and total EGFR levels. Overexpression of miR200c in PC-3 cells results in decreased expression of EGFR, ZEB1, ERK1/2 and Kaiso. Additionally, sh-Kaiso PC-3 demonstrates reduced in vivo tumor formation and metastasis. Thus, our data suggests that EGFR signaling regulates the silencing of miR-200 family through Kaiso binding to methylated regions in the promoter.
AB - The loss of miR-200 family, through DNA methylation, results in cancer cells undergoing an epithelial to mesenchymal transition (EMT), and metastasis. In this study, we established that the transcriptional repressor Kaiso directly binds methylated regions of the miR-200 family, and this is reversed with 5-aza treatment. sh-Kaiso PC-3 cells display increased miR-200-a/b/c, miR-141, and miR-429 expression, with miR-200c demonstrating the most significant increase. Interestingly, overexpression of EGFR or treatment with EGF decreases miR-200c expression and this is reversed after treatment with EGFR specific kinase inhibitor PD153035. However, EGF did not have a significant effect on miR-200c in sh-Kaiso DU-145 or PC-3 cell lines, suggesting Kaiso silences miR-200c through the activation of EGFR signaling. Overexpression of Kaiso in LNCaP cells results in decreased expression of miR-200-a/b/c, miR-141, and miR-429, along with increased expression of ZEB1, p-EGFR and total EGFR levels. Overexpression of miR200c in PC-3 cells results in decreased expression of EGFR, ZEB1, ERK1/2 and Kaiso. Additionally, sh-Kaiso PC-3 demonstrates reduced in vivo tumor formation and metastasis. Thus, our data suggests that EGFR signaling regulates the silencing of miR-200 family through Kaiso binding to methylated regions in the promoter.
KW - DNA methylation
KW - Epithelial to mesenchymal transition
KW - Kaiso
KW - Metastasis
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85054319530&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054319530&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2018.04.044
DO - 10.1016/j.canlet.2018.04.044
M3 - Article
C2 - 29751044
AN - SCOPUS:85054319530
SN - 0304-3835
VL - 431
SP - 1
EP - 10
JO - Cancer Letters
JF - Cancer Letters
ER -