SALL Proteins; Common and Antagonistic Roles in Cancer

Abstract

SALL proteins are a family of four conserved C2H2 zinc finger transcription factors that play critical roles in organogenesis during embryonic development. They regulate cell proliferation, survival, migration, and stemness; consequently, they are involved in various human genetic disorders and cancer. SALL4 is a well-recognized oncogene; however, SALL1-3 play dual roles depending on the cancer context and stage of the disease. Current reviews of SALLs have focused only on SALL2 or SALL4, lacking an integrated view of the SALL family members in cancer. Here, we update the recent advances of the SALL members in tumor development, cancer progression, and therapy, highlighting the synergistic and/or antagonistic functions they perform in similar cancer contexts. We identified common regulatory mechanisms, targets, and signaling pathways in breast, brain, liver, colon, blood, and HPV-related cancers. In addition, we discuss the potential of the SALL family members as cancer biomarkers and in the cancer cells' response to therapies. Understanding SALL proteins' function and relationship will open new cancer biology, clinical research, and therapy perspectives.

Keywords: PTEN; SALL1; SALL2; SALL3; SALL4; Wnt; biomarker; cancer; epigenetic regulation.

Figure 1

Schematic representation of the main SALL protein isoforms. The colors represent the different SALL proteins; yellow, blue, green, and red for SALL1, SALL2, SALL3, and SALL4, respectively. Dark grey rectangles at the N-terminal region represent the C2HC-type Zinc Finger Motif (ZF1). Light grey rectangles represent C2H2-type Zinc Finger Motifs 2–5 (ZF2–ZF5); all of them are in SALL1-A, SALL1-B, and SALL3. SALL4 lacks ZF4, and SALL2 has a motif that differs from the others, located between ZF4 and ZF5 (depicted as ZF4/5). The pink rectangle at the N-terminal region represents the conserved 12-amino-acid region that binds to the NuRD complex, named repression domain (RD). The RD is in SALL1A, SALL2 E1, SALL3, SALL4 A, B, and C. The yellow rectangle between ZF1 and ZF2 corresponds to the conserved Glutamine-rich (Q-rich) region. The circle at the N-terminal region shows the nuclear localization sequences (NLS) described only for SALL2 E1A, and SALL4 A and B. The ensembl transcript ID is under each isoform name in brackets. Exon representation is above each SALL protein, and the protein length is at the end of each isoform. ZF: Zinc Finger; Q-rich: Glutamine-rich; RD: Repression Domain; DBD: DNA Binding Domain; NLS: Nuclear Localization Sequence.

Figure 2

Common upstream regulation, partners, genes, and cellular functions of the SALL family. Epigenetic changes, including gene hypermethylation, hypomethylation, and miRs, are common mechanisms of SALL regulation. SALL1–3 promoters are hypermethylated in several cancers [54,55,92,93,94,95,96,97]. In contrast, the SALL4 promoter is hypomethylated in AML and MDS [98,99] and regulated by miRNAs in multiple cancer types [100]. Additionally, SALL1 and SALL2 are regulated by miRs (Table 1). Regulation by specific transcription factors depicted for SALL2 and SALL4. SALL proteins interact with specific partners to perform their functions; shared protein partners among the family include β-catenin and DNMT3. In addition, the four SALLs interact with the NuRD complex and with SOX2. Common transcriptional targets of SALLs are associated with cell proliferation and migration/invasion. SALL2 and SALL4 oppositely regulate CCDN1, c-MYC, and PTEN. Similarly, SALL1 and SALL4 oppositely regulate CDH1 (E-cadherin) and VIM (vimentin). However, SALL1 and SALL4 are both negative regulators of PTEN. Moreover, apoptosis-associated genes, such as BAX and PMAIP1 (NOXA), are regulated by SALL2. Green lines: positive regulation. Red lines: negative regulation. Dotted lines: proposed association.

Figure 3

SALL proteins in cancer. SALL proteins are deregulated in major cancer types, including lung, colon, and breast cancers. As shown above, independent studies identified alterations in more than one family member in specific cancer types. According to genetic alterations, isoform expression, and changes in their expression, they are classified as oncogenes (red), tumor suppressors (green), or genes with a dual role in cancer (yellow).