Mel-18 Acts as a Tumor Suppressor by Repressing Bmi-1 Expression and Down-regulating Akt Activity in Breast Cancer Cells

Abstract

The Bmi-1 oncogene is overexpressed in a number of malignancies including breast cancer. In addition to Bmi-1, mammalian cells also express four other polycomb group (PcG) proteins that are closely related to Bmi-1. Virtually nothing is known about the role of these PcG proteins in oncogenesis. We have recently reported that Mel-18, a Bmi-1-related PcG protein, negatively regulates Bmi-1 expression, and that its expression negatively correlates with Bmi-1 in proliferating and senescing human fibroblasts. Here, we report that the expression of Bmi-1 and Mel-18 inversely correlates in a number of breast cancer cell lines and in a significant number of breast tumor samples. Overexpression of Mel-18 results in repression of Bmi-1 and reduction of the transformed phenotype in malignant breast cancer cells. Furthermore, the repression of Bmi-1 by Mel-18 is accompanied by the reduction of Akt/protein kinase B (PKB) activity in breast cancer cells. Similarly, Bmi-1 knockdown using RNA interference approach results in down-regulation of Akt/PKB activity and reduction in transformed phenotype of MCF7 cells. Importantly, we show that overexpression of constitutively active Akt overrides tumor-suppressive effect of Mel-18 overexpression and the knockdown of Bmi-1 expression. Thus, our studies suggest that Mel-18 and Bmi-1 may regulate the Akt pathway in breast cancer cells, and that Mel-18 functions as a tumor suppressor by repressing the expression of Bmi-1 and consequently down-regulating Akt activity. [Cancer Res 2007;67(11):5083-9]

A feedback loop that regulates the expression of polycomb group protein Suz12 via non-canonical WNT signaling pathway in blast crisis of chronic myeloid leukemia

“…One of the mechanisms clearly recognized by which PcG proteins promote tumorigenesis is the increase in cell survival [6]. As it was previously reported, the RNAi knock-down of Kaiso in K562 cells improves survival and proliferation [3].…”

“…Thus, we imagine that Kaiso's displacement from the nucleus to the cytoplasmic compartment [3], thereby breaking the normal regulatory loop equilibrium could be responsible for triggering the super expression of Wnt5a/Wnt11, and consequently, the overexpression of Suz12 in the context of that cell set. Consistent with the rupture of regulatory loop equilibrium the PcG proteins overexpression seems to be a trademark for some types of tumors [5,6,9,10,20]. Particularly, the increase of Suz12 is one of the main features found in K562 cells used as the cellular model of chronic myeloid leukemia in a blast crisis [15].…”

“…These proteins are often aberrantly expressed in cancer cells and, in particular, Suz12, EZH2 and BMI1 are well known to be over-expressed in a certain number of human tumors including breast cancer, prostate cancer and chronic myeloid leukemia [5,6,9,10,15,20]. The principal mechanism by which PcG proteins promote tumorigenesis and metastasis seems to be senescence bypass [1,8] and increase cell survival [6,7]. Recent studies have shown that PcG proteins may also regulate cellular and oncogenic functions in a transcription repression-independent manner.…”

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

“…Much evidence has shown that these proteins have a crucial role in tumor development through regulating various cellular processes, such as cell proliferation, invasion and metastasis (Guo et al, 2007a). Although Mel-18 is 57% homologous to another polycomb repressive complex-1 group protein, Bmi-1, which has been implicated as a putative oncogene (Jacobs et al, 1999); it has been suggested that Mel-18 functions as a negative regulator of Bmi-1 via inhibiting c-Myc expression (Guo et al, 2007b). The role of Mel-18 in human cancer has not yet been fully revealed, but several studies have shown the tumor suppressive activity of Mel-18, unlike Bmi-1.…”

βTrCP regulates BMI1 protein turnover via ubiquitination and degradation

“…For example, BMI1 is overexpressed in a number of cancers including breast and prostate cancers. [2][3][4] In addition to its role in cancer, BMI1 is known to be required for self-renewal of neural, hematopoietic, intestinal and mammary stem cells. [5][6][7] It has been proposed that BMI1 overexpression promotes stem-ness in tumor cells, which promotes therapy resistance in cancer patients.…”