Mel-18 negatively regulates INK4a/ARF-independent cell cycle progression via Akt inactivation in breast cancer
- Authors
- Lee, Jeong-Yeon; Jang, Ki-Seok; Shin, Dong-Hui; Oh, M-Yun; Kim, Hyun-Jun; Kim, Yongseok; Kong, Gu
- Issue Date
- Jun-2008
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- CANCER RESEARCH, v.68, no.11, pp.4201 - 4209
- Indexed
- SCIE
SCOPUS
- Journal Title
- CANCER RESEARCH
- Volume
- 68
- Number
- 11
- Start Page
- 4201
- End Page
- 4209
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/172024
- DOI
- 10.1158/0008-5472.CAN-07-2570
- ISSN
- 0008-5472
- Abstract
- Mel-18, a polycomb group (PcG) protein, has been suggested as a tumor suppressor in human breast cancer. Previously, we reported that Mel-18 has antiproliferative activity in breast cancer cells. However, its functional mechanism has not been fully elucidated. Here, we investigated the role of Mel-18 in human breast cancer. We saw an inverse correlation between Mel-18 and phospho-Akt, which were expressed at low and high levels, respectively, in primary breast tumor tissues from 40 breast cancer patients. The effect of Mel-18 on cell growth was examined in two breast cancer cell lines, SK-BR-3 and T-47D, which express relatively low and high levels of endogenous Mel-18, respectively. On Mel-18 overexpression in SK-BR-3 cells, cell growth was attenuated and G(1) arrest was observed. Likewise, suppression of Mel-18 by antisense expression in T-47D cells led to enhanced cell growth and accelerated G(1)-S phase transition. In these cells, cyclin-dependent kinase (Cdk)-4 and Cdk2 activities were affected by Mel-18, which were mediated by changes in cyclin D1 expression and p27(Kip1) phosphorylation at Thr(157), but not by INK4a/ARF genes. The changes were both dependent on the phosphatidylinositol 3-kinase/Akt signaling pathway. Akt phosphorylation at Ser(473) was reduced by Mel-18 overexpression in SK-BR-3 cells and enhanced by Mel-18 suppression in T-47D cells. Akt-mediated cytoplasmic localization of p27(Kip1) was inhibited by Mel-18 in SK-BR-3 cells. Moreover, Mel-18 overexpression showed reduced glycogen synthase kinase-3 beta phosphorylation, beta-catenin nuclear localization, T-cell factor/lymphoid enhancer factor promoter activity, and cyclin D1 mRNA level. Taken together, we established a linear relationship between Mel-18 -> Akt -> G(1) phase regulators.
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