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.

Structural studies of SALL family protein zinc finger cluster domains in complex with DNA reveal preferential binding to an AATA tetranucleotide motif

“…Very recently, two lines of work independently identified Spalt-like transcription factor 4 (SALL4) as the AT-rich DNA-binding protein via pull-down mass spectrometry screen and protein binding microarray, respectively ( 14 , 15 ). SALL4 belongs to the Spalt-like transcription factors (SALLs) family, which includes SALL1-4 ( 16 ). Both SALL1 and SALL3 contain four zinc finger clusters (ZFCs), termed as ZFC1-4, whereas SALL2 and SALL4 contain three ZFCs and lack ZFC4 and ZFC3, respectively ( 14 ).…”

Convergence of specified RUNX2, SALL1, and SAMD9 variants permits normal global immune and endocrine function despite bone marrow hypocellularity and reduced ovarian reserve

“…Mammalian estrogen receptor β (ERβ) is required for ovarian follicles to advance past the antral stage, and work in rat granulosa cells has placed RUNX2 within the ERβ-regulated genes directing folliculogenesis, oocyte maturation, and ovulation [36]. While SALL1 is essential for stem cell maintenance in kidney, heart, and spermatogonial progenitors [4,37], its role in human ovarian tissue awaits better characterization. Should undetectable serum AMH persist and ovarian histology be normal, this patient may consider fertility treatment including platelet-rich plasma for 'ovarian rejuvenation ' [38] as an alternative to donor egg IVF.…”

“…This gene also coordinates female urogenital structure, and Mullerian defects can occur with its mutation [3]. SALL1 also modulates human tumorigenesis with > 70 variants now associated with Townes-Brocks syndrome (i.e., otic, limb, renal, and anal anomalies) [4]. Such mutations occur with uncertain frequency, but from > 3,000 targets with putative association to single gene disorders, SALL1 was among the least common [5].…”

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

“…The E1 isoform is restricted to specific tissues, such as the brain, kidney, thymus, testis, and colon, while E1A has ubiquitous expression ( Ma et al, 2001 ; Hermosilla et al, 2017 ). SALL2 was associated with development, neuronal differentiation, and cancer ( Hermosilla et al, 2017 ; Álvarez et al, 2021 ). SALL2 deregulates in various cancer types, but its role in the disease is not entirely understood.…”