Developmental SALL2 transcription factor: a new player in cancer

Abstract

SALL2, also known as Spalt-like transcription factor 2, is a member of the SALL family of transcription factors involved in development and conserved through evolution. Since its identification in 1996, findings indicate that SALL2 plays a role in neurogenesis, neuronal differentiation and eye development. Consistently, SALL2 deficiency associates with neural tube defects and coloboma, a congenital eye disease. Relevant to cancer, clinical studies indicate that SALL2 is deregulated in various cancers and is a specific biomarker for Synovial Sarcoma. However, the significance of SALL2 deregulation in this disease is controversial. Here, we present and discuss all available information about SALL2 since its discovery, including isoforms, regulation, targets and functions. We specifically discuss the role of SALL2 in the regulation of cell proliferation and survival within the context of the identified target genes, its interaction with viral oncogenes, and its association with the TP53 tumor suppressor and MYC oncogene. Special attention is given to p53-independent SALL2 regulation of pro-apoptotic genes BAX and PMAIP1, and the implication of these findings on the apoptotic response of cancer cells to therapy. Understanding SALL2 function and the molecular mechanisms governing its expression and activity is critical to comprehend why and how SALL2 could contribute to disease. This knowledge will open new perspectives for the development of molecular targeted approaches in disease.

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

“…1). Type 3 fusion was characterized by genes fused to TCR-alpha, -beta, or -delta (TRA/ TRB/TRD) loci, leading to overexpression of SALL2 [a TF deregulated in various cancers (27)] and NKX2-1 (SI Appendix, Fig. S3C).…”

Epigenetic silencing of SALL 2 confers tamoxifen resistance in breast cancer

“…Of importance, we found that SALL2 expression was significantly decreased in relapsed metastatic tumors compared to the paired primary tumors ( Fig 1G). Moreover, two alternative splice transcripts of SALL2, E1 and E1A, have been identified previously (Hermosilla et al, 2017). Analysis of the collected breast cancer tissues and of a TCGA breast cancer dataset revealed that only the E1A isoform of SALL2 was expressed in breast cancer samples (Appendix Fig S2A and B).…”

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

“…These two isoforms differ in the first 25 amino acids , and those amino acids are particularly relevant as SALL2-E1 contains a 12 amino acids conserved motif involved in transcriptional repression through its interaction with the NuRD complex (Lauberth and Rauchman, 2006). Both SALL2 isoforms contain several C 2 H 2 zinc finger motifs along the structure, and several glutamine-, serine-, and proline-rich regions, which are typically present in transcription factors (Hermosilla et al, 2017). E1 is restricted to certain tissues such as thymus, testis, and colon, while E1A has ubiquitous expression.…”

“…Consequently, SALL2/Sall2 deficiency associates with neural tube defects in mice, and with coloboma, a congenital eye disease in humans and mice (B€ ohm et al, 2008;Kelberman et al, 2014). Importantly, SALL2 is deregulated and/or mutated in various cancers, suggesting a role for SALL2 in the disease (Hermosilla et al, 2017). In this context, most findings suggest that SALL2 behaves as a tumor suppressor (Hermosilla et al, 2017;Sung and Yim, 2017).…”

“…Importantly, SALL2 is deregulated and/or mutated in various cancers, suggesting a role for SALL2 in the disease (Hermosilla et al, 2017). In this context, most findings suggest that SALL2 behaves as a tumor suppressor (Hermosilla et al, 2017;Sung and Yim, 2017). Like the retinoblastoma protein (pRb) and the p53 tumor suppressors (Yim and Park, 2005), SALL2 interacts with viral oncogenic proteins.…”