C-terminal binding protein-2 promotes cell proliferation and migration in breast cancer via suppression of p16INK4A.

Xiaojing Yang,Weiwei Yu,Yuhui Shao,Jie Fu,Hongling Li,Yi Sun,Depeng Zhao

doi:10.18632/oncotarget.15402

Abstract

C-terminal binding protein-2 (CtBP2) enhances cancer proliferation and metastasis. The role and mechanism of CtBP2 in breast cancer remains to be elucidated. Western blot and immunochemistry were employed to evaluate the level of CtBP2 and p16INK4A in breast cancer. Genetic manipulation was used to study the expression of p16INK4A and its downstream genes regulated by CtBP2. Functional assays, including colony formation, wound healing, transwell invasion, anchorage-independent growth assay and a xenograft tumor model were used to determine the oncogenic role of CtBP2 in breast cancer progression. The expression of CtBP2 was increased in breast cancer tissues and cell lines. The expression of p16INK4A were inversely correlated CtBP2 (r2 = 0.43, P < 0.01). The expression of both CtBP2 and p16INK4A were significantly related to histological differentiation (P < 0.01 and P = 0.004, respectively) and metastasis (P = 0.046 and 0.047, respectively). The overall survival rate was lower in patients with increased CtBP2 expression and lower p16INK4A expression. Knockdown of CtBP2 resulted in the activation of p16INK4A and down–regulation of cell cycle regulators cyclin D, cyclin E and cyclin-dependent kinase 2 and 4. This down-regulation also led to a decreased transition of the G1-S phase in breast cancer cells. Moreover, gain-of-function experiments showed that CtBP2 suppressed p16INK4A and matrix metalloproteinase-2, subsequently enhancing the migration in breast cancer. However, the silence of CtBP2 abrogated this effect. Collectively, these findings provide insight into the role CtBP2 plays in promoting proliferation and migration in breast cancer by the inhibition of p16INK4A.

Highlights

Breast cancer is currently one of the most common malignancies, and the second leading cause of cancer death among women worldwide [1]
The expression of C-terminal binding protein-2 (CtBP2) was higher in MDA-MB-231 and MCF-7 cells when compared with other cell lines (Figure 1C, 1D)
Our findings suggest that CtBP2 promotes cell proliferation by inhibiting p16INK4A, resulting in a shorter transition of the cell cycle in breast cancer cells

Summary

Introduction

Breast cancer is currently one of the most common malignancies, and the second leading cause of cancer death among women worldwide [1]. Despite the progress in combined modality therapies, the long-term outcome of patients with breast cancer is far from satisfactory [2]. This outcome is mainly attributed to the induction and progression of breast cancer. Several studies show that aberrant transcriptional activities of major oncogenes and tumor suppressor genes are involved in the tumorigenesis of breast cancer [3]. C-terminal binding protein family proteins (CtBP1 and CtBP2), members of the co-repressors family, are reported to be involved in several essential cellular processes related to tumorigenesis [4]. The expression of CtBP2 is increased in patients with malignant cancers [10,11,12,13,14], and associated with a poorer prognosis

Methods

Results

Conclusion