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

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.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0824-y) contains supplementary material, which is available to authorized users.

p38 and Casein Kinase 2 Mediate Ribonuclease 1 Repression in Inflamed Human Endothelial Cells via Promoter Remodeling Through Nucleosome Remodeling and Deacetylase Complex

“…MAPK signaling cascades are known to be highly involved in chromatin remodeling and subsequent gene regulation, for instance via phosphorylation of transcription factors that further influence recruitment of the polymerase II transcription machinery, histone acetyl transferase complexes, as well as chromatin remodeling and HDAC complexes ( Suganuma and Workman, 2011 ). In this context, TNF-α-induced p38 signaling was shown to promote the interaction of transcription factor YY1 and the polycomb repressive complex 2 to induce repressive chromatin structures at target gene promoters ( Palacios et al, 2010 ), while tumor suppressor SALL1 induces p38-dependent NuRD recruitment to promote cancer cell senescence ( Ma et al, 2018 ). Although transcription factors involved in RNase1 repression are still unknown, these findings are in line with the presented observations that TNF-α-induced p38 signaling is critical for recruitment of the NuRD/CHD4 complex to the RNASE1 promoter to conduct H4 and H3K27 deacetylation and RNASE1 repression.…”

Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases

“…S12B). Previous studies have reported that SALL1 can recruit histone deacetylase (HDAC) to mediate transcriptional repression and that its promoter is often methylated in BCP ALL (22,23). ZEB2 is a member of the Zfh1 family of two-handed zinc-finger/ homeodomain proteins.…”

SALL4 promotes tumor progression in breast cancer by targeting EMT

“…There has been only one previous study investigating the overexpression of SALL4 in breast cancer and it indirectly demonstrated that overexpression of SALL4 did not have significant enhancement on cell proliferation. 31 There was no significant difference in IC 50 of DOX in B8 or G3 either (205 ± 13) was about three-fold higher than that of the vector control group (62 ± 8) and parental cells (50 ± 14) ( Figure 3D). Migration ability was also enhanced after SALL4 was overexpressed ( Figure 3E,F).…”