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The ETS transcription factor MEF is a candidate tumor suppressor gene on the X chromosome
Yoshiyuki Seki1, Mary Ann Suico, Ayako Uto
1Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Abstract:
Although X chromosome transfer experiments indicated that tumor suppressor genes are present on the X chromosome, they have not been previously identified. In this report, we show that the ETS transcription factor MEF (ELF4), which is located on chromosome Xq26.1, possesses tumor suppressive capability. MEF expression was up-regulated by 5-azacytidine in some cancer cell lines. MEF overexpression induced morphological changes, such as the conversion of normally loose cell-cell contacts to strong interactions similar to those seen in the presence of matrix metalloproteinase (MMP) inhibitor BB94. In the colony formation assay, A549 cells, but not MEF-overexpressing cells, formed colonies in soft agar culture. Furthermore, MEF-overexpressing cells s.c. injected in the nude mice did not grow, whereas the control cells did. The A549 tumors were poorly differentiated, whereas the MEF-overexpressing tumors were well differentiated. By immunostaining with CD31, a marker on vascular endothelial cells, we found that tumor angiogenesis was significantly suppressed in the tumors formed from MEF-overexpressing cells. In addition, the conditioned media from A549 cell cultures stimulated the migration of human umbilical vein endothelial cells, whereas conditioned media from MEF-overexpressing cell cultures had less of an effect. By gelatin zymography, Western blotting analysis, and immunohistochemistry, we found that the expression levels of MMP-9 and MMP-2 were significantly reduced in MEF-overexpressing tumors. Immunohistochemical analyses showed that interleukin (IL)-8 expression was reduced in the MEF-overexpressing tumors in nude mice. Furthermore, IL-8 mRNA expression in vitro was significantly down-regulated in MEF-overexpressing cells, compared with A549 cells. MEF suppressed the transcription and promoter activities of the genes encoding MMP-9 and IL-8, whereas ETS-2 up-regulated these activities. Therefore, we propose that MEF is a candidate tumor suppressor gene on the X chromosome with activities that are opposite to those of ETS-2.
Insights
The ETS transcription factor MEF (ELF4) on the X chromosome acts as a tumor suppressor. MEF overexpression inhibits tumor growth, angiogenesis, and matrix metalloproteinase (MMP) and interleukin-8 (IL-8) expression.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- X chromosome transfer experiments suggest the presence of tumor suppressor genes.
- Tumor suppressor genes on the X chromosome have not been definitively identified.
Purpose of the Study:
- To identify and characterize a novel tumor suppressor gene on the X chromosome.
- To investigate the role of the ETS transcription factor MEF (ELF4) in tumor suppression.
Main Methods:
- MEF expression analysis in cancer cell lines treated with 5-azacytidine.
- Assessing MEF overexpression effects on cell morphology, colony formation, and tumor growth in nude mice.
- Evaluating MEF's impact on tumor angiogenesis, matrix metalloproteinase (MMP) and interleukin-8 (IL-8) expression, and their respective gene transcription.
Main Results:
- MEF (ELF4) located on Xq26.1 exhibits tumor suppressive capabilities.
- MEF overexpression induced cell-cell adhesion, inhibited soft agar colony formation, and prevented tumor growth in vivo.
- MEF suppressed tumor angiogenesis, reduced MMP-9, MMP-2, and IL-8 expression, and inhibited their gene transcription, opposing ETS-2 activity.
Conclusions:
- MEF (ELF4) is a candidate tumor suppressor gene on the X chromosome.
- MEF suppresses tumor progression by inhibiting angiogenesis and key pro-tumorigenic factors like MMPs and IL-8.