SALL1 functions as a tumor suppressor in breast cancer by regulating cancer cell senescence and metastasis through the NuRD complex

Molecular Cancer

Guangyong Peng¹  Fang Wang¹  Susan M. Kiefer¹  Bing Han¹  Fusheng Si¹  Chunling Ma¹  Jian Ye¹  Xiaoli Zhong¹  Mark A. Varvares²  Pamela Hunborg³  Eddy C. Hsueh³  Yanping Zhang³  Lynn Robbins⁴  Michael Rauchman⁴ 

[1] Department of Internal Medicine, Saint Louis University School of Medicine;Department of Otolaryngology, Saint Louis University School of Medicine;Department of Surgery, Saint Louis University School of Medicine;VA Saint Louis Health Care System, John Cochran Division;

关键词: SALL1;    Tumor suppressor gene;    Senescence;    NuRD complex;    Tumorigenesis;    Metastasis;   

DOI  :  10.1186/s12943-018-0824-y

来源: DOAJ

【 摘 要 】

Abstract Background SALL1 is a multi-zinc finger transcription factor that regulates organogenesis and stem cell development, but the role of SALL1 in tumor biology and tumorigenesis remains largely unknown. Methods We analyzed SALL1 expression levels in human and murine breast cancer cells as well as cancer tissues from different types of breast cancer patients. Using both in vitro co-culture system and in vivo breast tumor models, we investigated how SALL1 expression in breast cancer cells affects tumor cell growth and proliferation, metastasis, and cell fate. Using the gain-of function and loss-of-function strategies, we dissected the molecular mechanism responsible for SALL1 tumor suppressor functions. Results We demonstrated that SALL1 functions as a tumor suppressor in breast cancer, which is significantly down-regulated in the basal like breast cancer and in estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) triple negative breast cancer patients. SALL1 expression in human and murine breast cancer cells inhibited cancer cell growth and proliferation, metastasis, and promoted cell cycle arrest. Knockdown of SALL1 in breast cancer cells promoted cancer cell growth, proliferation, and colony formation. Our studies revealed that tumor suppression was mediated by recruitment of the Nucleosome Remodeling and Deacetylase (NuRD) complex by SALL1, which promoted cancer cell senescence. We further demonstrated that the mechanism of inhibition of breast cancer cell growth and invasion by SALL1-NuRD depends on the p38 MAPK, ERK1/2, and mTOR signaling pathways. Conclusion Our studies indicate that the developmental control gene SALL1 plays a critical role in tumor suppression by recruiting the NuRD complex and thereby inducing cell senescence in breast cancer cells.

【 授权许可】

Unknown