Abstract
BackgroundSALL1 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.MethodsWe 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.ResultsWe 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.ConclusionOur 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.
Highlights
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
We further revealed that SALL1 tumor suppressor activity depended on its ability to recruit Nucleosome Remodeling and Deacetylase (NuRD) and that this molecular process was controlled by MAPK p38 and ERK1/2, and mTOR signaling pathways in cancer cells
SALL1 expression is down-regulated in human breast cancer cell lines and tissues We investigated whether SALL1 could function as a tumor suppressor and dissected the molecular mechanism by which it regulates human breast cancer
Summary
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. The SALL family are zinc finger transcription factors that were shown to function as critical regulators in the development of multiple mammalian organs, including kidney, heart, and the hematopoietic system [4,5,6]. Besides the regulation of organ and stem cell development, the role of SALL genes in tumor biology and tumorigenesis has been recently investigated. A recent report identified SALL1 as a tumor suppressor in human breast cancer, using an in vivo RNAi screen strategy [20]. The molecular mechanism and causative role of SALL1 in the regulation of breast cancer development and tumorigenesis are not well understood
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