Research

SETDB1 accelerates tumourigenesis by regulating the WNT signalling pathway (J. Pathol, Dec 2014)

Qiao-Yang Sun,1,# Ling-Wen Ding,1,#,* Jin-Fen Xiao,1,# Wenwen Chien,1 Su-Lin Lim,1 Norimichi Hattori,1 Lee Goodglick,3,4 David Chia,3 Vei Mah,3 Mohammad Alavi,3 Sara R Kim,3 Ngan B Doan,5 Jonathan W Said,5 Xin-Yi Loh,1 Liang Xu,1 Li-Zhen Liu,1 Henry Yang,1 Takahide Hayano,1 Shuo Shi,6 Dong Xie,1 De-Chen Lin1,2 and H Phillip Koeffler1,2

1 Cancer Science Institute of Singapore, National University of Singapore, Singapore
2 Division of Hematology/Oncology, Cedar–Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA
3 Departments of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
4 California NanoSystems Institute, University of California, Los Angeles, CA, USA
5 Los Angeles Medical Center, University of California at Santa Monica, Los Angeles, CA, USA
6 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of Chinese Academy of Sciences, Shanghai, People’s Republic of China

We investigated the oncogenic role of SETDB1, focusing on non-small cell lung cancer (NSCLC), which has high expression of this protein. A total of 387 lung cancer cases were examined by immunohistochemistry; 72% of NSCLC samples were positive for SETDB1 staining, compared to 46% samples of normal bronchial epithelium (106 cases) (p <0.0001). The percentage of positive cells and the intensity of staining increased significantly with increased grade of disease. Forced expression of SETDB1 in NSCLC cell lines enhanced their clonogenic growth in vitro and markedly increased tumour size in a murine xenograft model, while silencing (shRNA) SETDB1 in NSCLC cells slowed their proliferation. SETDB1 positively stimulated activity of the WNT–B-catenin pathway and diminished P53 expression, resulting in enhanced NSCLC growth in vitro and in vivo. Our finding suggests that therapeutic targeting of SETDB1 may benefit patients whose tumours express high levels of SETDB1.

jpathol

Schematic illustration of the proposed signalling interaction of SETDB1 and the WNT pathway.