SALL2 represses cyclins D1 and E1 expression and restrains G1/S cell cycle transition and cancer‐related phenotypes

Abstract

SALL2 is a poorly characterized transcription factor that belongs to the Spalt‐like family involved in development. Mutations on SALL2 have been associated with ocular coloboma and cancer. In cancers, SALL2 is deregulated and is proposed as a tumor suppressor in ovarian cancer. SALL2 has been implicated in stemness, cell death, proliferation, and quiescence. However, mechanisms underlying roles of SALL2 related to cancer remain largely unknown. Here, we investigated the role of SALL2 in cell proliferation using mouse embryo fibroblasts (MEFs) derived from Sall2 −/− mice. Compared to Sall2 +/+ MEFs, Sall2 −/− MEFs exhibit enhanced cell proliferation and faster postmitotic progression through G1 and S phases. Accordingly, Sall2 −/− MEFs exhibit higher mRNA and protein levels of cyclins D1 and E1. Chromatin immunoprecipitation and promoter reporter assays showed that SALL2 binds and represses CCND1 and CCNE1 promoters, identifying a novel mechanism by which SALL2 may control cell cycle. In addition, the analysis of tissues from Sall2 +/+ and Sall2 −/− mice confirmed the inverse correlation between expression of SALL2 and G1‐S cyclins. Consistent with an antiproliferative function of SALL2, immortalized Sall2 −/− MEFs showed enhanced growth rate, foci formation, and anchorage‐independent growth, confirming tumor suppressor properties for SALL2. Finally, cancer data analyses show negative correlations between SALL2 and G1‐S cyclins’ mRNA levels in several cancers. Altogether, our results demonstrated that SALL2 is a negative regulator of cell proliferation, an effect mediated in part by repression of G1‐S cyclins’ expression. Our results have implications for the understanding and significance of SALL2 role under physiological and pathological conditions.

Haploinsufficiency of Insm1 Impairs Postnatal Baseline β-Cell Mass

“…The Ccnd1 gene is regulated at the transcriptional and translational levels (27)(28)(29). We found that Ccnd1 transcription is dependent on Insm1 dosage, and the protein level is also decreased in b-cells of Insm +/lacZ mice.…”

The uncharacterized protein FAM47E interacts with PRMT5 and regulates its functions

“…Because FAM47E regulates the PRMT5-mediated epigenetic regulation, we investigated the binding of FAM47E and PRMT5 at the promoters of the tested PRMT5 target genes by using chromatin immunoprecipitation (ChIP). The details about the promoter regions of these genes for ChIP analyses were obtained from previous studies ( Khan et al, 2007 ; Oconnell et al, 2015 ; Rubino et al, 2017 ; Hermosilla et al, 2018 ; Lee et al, 2019 ). We found that both FAM47E and PRMT5 proteins were enriched at the promoter regions of the tested PRMT5 target genes.…”

Synergistic inhibition of csal1 and csal3 in granulosa cell proliferation and steroidogenesis of hen ovarian prehierarchical development†

“…SALL1 expression in human and murine breast cancer cells inhibited cancer cell growth and proliferation, whereas knockdown of SALL1 in breast cancer cells promoted cancer cell growth and proliferation [42]. Moreover, SALL2 can suppress tumorigenesis through cell cycle inhibition and induction of apoptosis [50], and the latest study proved that SALL2 is a negative regulator of cell proliferation [19]. In the current study, we found that overexpression of csal1 / csal3 gene in the GCs contributed to a significant decrease in cell proliferation ( P < 0.01).…”

“…The SALL proteins have been described as transcriptional repressors because the N-terminal region of the protein contains a highly conserved 12-amino acid motif, which is sufficient for the recruitment of nucleosome remodeling and deacetylase corepressor complex (NuRD) [28], of which SALL1 is capable of binding to β-catenin and activates synergistically a reporter construct responding to the Wnt signaling pathway through recruitment of remodeling factors to heterochromatin [29]. Moreover, SALL2 binds and represses CCND1 promoters and is recognized as a novel mechanism by which SALL2 exerts a negative regulatory role in cell proliferation associated with the regulation of cell cycle progression [19]. SALL2 is deregulated and is proposed as a tumor suppressor in human ovarian cancer [17, 18, 30].…”