LncRNA DILA1 inhibits Cyclin D1 degradation and contributes to tamoxifen resistance in breast cancer

Qianfeng Shi,Ying Li,Erwei Song,Qian Li,Yanqing Wu,Yudong Li,Qiang Liu,Shunying Li,Zongqi Wu,Mengdi Zhu,Zijie Cai,Liang Jin,Yujie Liu,Jingru Wang,Hongna Lai

doi:10.1038/s41467-020-19349-w

Abstract

Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer. Here, we identify a lncRNA, DILA1, which interacts with Cyclin D1 and is overexpressed in tamoxifen-resistant breast cancer cells. Mechanistically, DILA1 inhibits the phosphorylation of Cyclin D1 at Thr286 by directly interacting with Thr286 and blocking its subsequent degradation, leading to overexpressed Cyclin D1 protein in breast cancer. Knocking down DILA1 decreases Cyclin D1 protein expression, inhibits cancer cell growth and restores tamoxifen sensitivity both in vitro and in vivo. High expression of DILA1 is associated with overexpressed Cyclin D1 protein and poor prognosis in breast cancer patients who received tamoxifen treatment. This study shows the previously unappreciated importance of post-translational dysregulation of Cyclin D1 contributing to tamoxifen resistance in breast cancer. Moreover, it reveals the novel mechanism of DILA1 in regulating Cyclin D1 protein stability and suggests DILA1 is a specific therapeutic target to downregulate Cyclin D1 protein and reverse tamoxifen resistance in treating breast cancer.

Highlights

Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer
There was no difference in Cyclin D1 mRNA levels between parental and resistant cells (Fig. S1c), indicating post-transcriptional or posttranslational changes may be responsible for the upregulated Cyclin D1 protein in tamoxifen-resistant breast cancer cells
It was found that small interfering RNAs (siRNAs) targeting Cyclin D1 restored tamoxifen sensitivity in MCF7-Re and T47D-Re cells (Fig. 1b and S1g), and resulted in cell cycle arrest at G1 phase (Fig. S1h, i), indicating that these tamoxifen-resistant breast cancer cells are still dependent on Cyclin D1 for cell cycle progression and upregulated Cyclin D1 is responsible for their tamoxifen resistance

Summary

Introduction

Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer. Upregulated Cyclin D1 protein is responsible for tamoxifen resistance in ER-positive breast cancer cells. DILA1-ASOs significantly increased ubiquitinated Cyclin D1 in MCF7-Re cells (Fig. 3i), suggesting that DILA1 inhibits the ubiquitination of Cyclin D1 and leads to upregulated Cyclin D1 protein in tamoxifen-resistant breast cancer cells.

Results

Conclusion