The Sall2 transcription factor promotes cell migration regulating focal adhesion turnover and integrin β1 expression

Abstract

SALL2/Sall2 is a transcription factor associated with development, neuronal differentiation, and cancer. Interestingly, SALL2/Sall2 deficiency leads to failure of the optic fissure closure and neurite outgrowth, suggesting a positive role for SALL2/Sall2 in cell migration. However, in some cancer cells, SALL2 deficiency is associated with increased cell migration. To further investigate the role of Sall2 in the cell migration process, we used immortalized Sall2 knockout (Sall2−/−) and Sall2 wild-type (Sall2+/+) mouse embryonic fibroblasts (iMEFs). Our results indicated that Sall2 positively regulates cell migration, promoting cell detachment and focal adhesions turnover. Sall2 deficiency decreased cell motility and altered focal adhesion dynamics. Accordingly, restoring Sall2 expression in the Sall2−/− iMEFs by using a doxycycline-inducible Tet-On system recovered cell migratory capabilities and focal adhesion dynamics. In addition, Sall2 promoted the autophosphorylation of Focal Adhesion Kinase (FAK) at Y397 and increased integrin β1 mRNA and its protein expression at the cell surface. We demonstrated that SALL2 increases ITGB1 promoter activity and binds to conserved SALL2-binding sites at the proximal region of the ITGB1 promoter, validated by ChIP experiments. Furthermore, the overexpression of integrin β1 or its blockade generates a cell migration phenotype similar to that of Sall2+/+ or Sall2−/− cells, respectively. Altogether, our data showed that Sall2 promotes cell migration by modulating focal adhesion dynamics, and this phenotype is associated with SALL2/Sall2-transcriptional regulation of integrin β1 expression and FAK autophosphorylation. Since deregulation of cell migration promotes congenital abnormalities, tumor formation, and spread to other tissues, our findings suggest that the SALL2/Sall2-integrin β1 axis could be relevant for those processes.

Casein kinase 2 phosphorylates and induces the SALL2 tumor suppressor degradation in colon cancer cells

“…Understanding mechanisms involved in regulating transcription factors’ activity is essential because of their role in gene expression and, ultimately, in cell behavior. SALL2 is a transcription factor involved in cell development, cell cycle arrest, apoptosis, cell migration, and disease [ 14 , 16 , 19 , 21 , 78 ]. SALL2 is downregulated or upregulated in cancer depending on the cancer type and stage.…”

“…Five thousand cells were seeded on 96-well plates and incubated with increasing concentrations of Silmitarsertib (0–40 μM) for 24 h at 37 °C. Cells were stained with 0,01% (p/v) crystal violet [ 19 ] and fluorescence (680 nm) was quantified using LI-COR ODYSSEY CLX equipment.…”

“…SALL2/Sall2 is involved in the proper closure of the neural tube and the optic fissure [ 10 , 11 ], morphological differentiation of hippocampal neurons [ 12 ], stemness maintenance of conjunctival epithelial stem cells [ 13 ], inhibition of DNA synthesis and entry into quiescence [ 14 ], promotion of cell death under genotoxic stimuli [ 15 – 17 ], and cell migration of cancer cells and embryonic fibroblasts [ 7 – 19 ]. SALL2 binds to the cognate sequence GGG(T/C)GGG in promoters of target genes [ 15 ].…”

“…SALL2 binds to the cognate sequence GGG(T/C)GGG in promoters of target genes [ 15 ]. Specifically, it binds and activates promoters of cell cycle inhibitors p21 ( CDKN1A ) and p16 ( CDKN2A ), proapoptotic genes such as BAX and NOXA ( PMAIP1 ) [ 8 , 15 , 16 , 20 ], and Integrin β1 ( ITGβ1) [ 19 ], a membrane receptor involved in cell adhesion and a variety of processes including embryogenesis, tissue repair, and cancer progression. SALL2 also represses promoters of the oncogenes MYC ( c-MYC) , Cyclin D1 ( CCND1 ), and Cyclin E1 ( CCNE1 ) [ 21 , 22 ].…”

Asociación de SALL2 y vía WNT/β-CATENINA en cáncer de colon

“…Actua como represor transcripcional de oncogenes como c-MYC, CCDN1 y CCNE1 (Hermosilla et al, 2018;Sung et al, 2012), y como activador de la transcripción de PTEN, CDKN1A, CDKN2A, BAX, PMAIP1, ESR1 e ITG1 D. Li et al, 2004;Parroche et al, 2011;Riffo et al, 2022;Wu et al, 2015;Ye et al, 2019). SALL2 actúa como un freno en la fase G1-S del ciclo celular, evidenciado por su regulación positiva de inhibidores de complejos…”