Cyclin D1 down-regulation is essential for DBC2’s tumor suppressor function

Abstract

The expression of tumor suppressor gene DBC2 causes certain breast cancer cells to stop growing [M. Hamaguchi, J.L. Meth, C. Von Klitzing, W. Wei, D. Esposito, L. Rodgers, T. Walsh, P. Welcsh, M.C. King, M.H. Wigler, DBC2, a candidate for a tumor suppressor gene involved in breast cancer, Proc. Natl. Acad. Sci. USA 99 (2002) 13647-13652]. Recently, DBC2 was found to participate in diverse cellular functions such as protein transport, cytoskeleton regulation, apoptosis, and cell cycle control [V. Siripurapu, J.L. Meth, N. Kobayashi, M. Hamaguchi, DBC2 significantly influences cell cycle, apoptosis, cytoskeleton, and membrane trafficking pathways. J. Mol. Biol. 346 (2005) 83-89]. Its tumor suppression mechanism, however, remains unclear. In this paper, we demonstrate that DBC2 suppresses breast cancer proliferation through down-regulation of Cyclin D1 (CCND1). Additionally, the constitutional overexpression of CCND1 prevented the negative impact of DBC2 expression on their growth. Under a CCND1 promoter, the expression of CCNE1 exhibited the same protective effect. Our results indicate that the down-regulation of CCND1 is an essential step for DBC2's growth suppression of cancer cells. We believe that this discovery contributes to a better understanding of DBC2's tumor suppressor function.

RhoBTB2 (DBC2) functions as tumor suppressor via inhibiting proliferation, preventing colony formation and inducing apoptosis in breast cancer cells

“…The growth inhibition effect of RhoBTB2 might be related to the down-regulation of cyclin D1. Yoshihara et al (2007) have demonstrated that RhoBTB2 can negatively regulate cell-cycle protein cyclin D1 in a posttranscriptional manner and the down-regulation of cyclin D1 leads to the growth suppression of cancer cells (Berthold et al, 2008).…”

RhoBTB2 (DBC2) Is a Mitotic E2F1 Target Gene with a Novel Role in Apoptosis

“…Further studies asserted that RhoBTB2-mediated down-regulation of cyclin D1 was obligatory for this effect (41). Another study utilizing pathway-based analysis of gene expression patterns found RhoBTB2 to effect the expression of genes associated with cell cycle, apoptosis, cytoskeleton and membrane-trafficking pathways (40).…”

“…An elegant study by Wilkins et al (39) identified RhoBTB2 as a substrate for the Cul3 ubiquitin ligase complex, and that point mutants of RhoBTB2 derived from human malignancy were unable to bind Cul3, therefore elevating RhoBTB2 expression due to decreased degradation. A more recent study looking into the biochemistry behind the growth inhibitory effect of RhoBTB2 in breast cancer samples identified cyclin D1 as being down-regulated following RhoBTB2 overexpression, suggesting a molecular target for the growth inhibitory effect of RhoBTB2 (41). Whether cyclin D1 is a direct or indirect target of RhoBTB2/Cul3 remains unclear.…”

Atypical Rho Family Members

“…RhoBTB2 inhibits cell proliferation in a breast cancer cell line lacking endogenous RhoBTB2 expression (Hamaguchi et al 2002), at least in part by inducing a decrease in Cyclin D1 levels (Yoshihara et al 2007). On the other hand, RhoBTB2 is a target of the E2F1 transcription factor, which contributes to cell cycle progression (Freeman et al 2008).…”