SALL4B, not targeted by IMiD, is important for SALL4-mediated tumorigenesis

Abstract

Oncofetal transcription factor SALL4 is essential for cancer cell survival. Recently, several groups reported that immunomodulatory imide drugs (IMiDs) could degrade SALL4 in a proteasome-dependent manner.6,7 Intriguingly, we observed that IMiDs had no effect on SALL4-positive cancer cells. Further studies demonstrated that IMiDs could only degrade SALL4A, one of the SALL4 isoforms. This finding raises the possibility that SALL4B, the isoform not affected by IMiDs, may be essential for SALL4-mediated cancer cell survival. SALL4B knockdown led to an increase in apoptosis and inhibition of cancer cell growth. SALL4B gain-of-function alone led to liver tumor formation in mice. Our observation that protein degraders can possess isoform-specific effects exemplifies the importance of delineating drug action and oncogenesis at the isoform level to develop more effective cancer therapeutics.

Targeting transcription factors through an IMiD independent zinc finger domain

“…Overall, our phenotypic screening results support that SH6 can selectively target cancer cell survival mediated by SALL4. More recently, in other studies, the dependency on SALL4 in SNU398 cells was demonstrated through a shRNA-medicated knock down approach (Vu et al, 2023) where we down-regulated either total SALL4 (both A and B) or SALL4B only in SNU398 cells. We observed that upon SALL4/SALL4B-specific knockdown, the apoptotic population of SNU398 cells was increased by 40%, and the cellular growth ability of these cells were significantly inhibited tested by soft agar colony formation and clonogenic assays.…”

“…3B). We have recently found that depletion of SALL4B is required for targeting SALL4-mediated tumorigenesis (Vu et al, 2023). To further examine the effect of IMiDs and SH6 in degrading SALL4B, SALL4B was fused to NanoLuc (Lu et al, 2014) and stably transfected into H1299 cells.…”

“…We recently observed that although IMiDs are capable of degrading SALL4A through ZFC2, they do not target the SALL4B isoform. As a result, IMiDs demonstrate no effectiveness in viability of cancer cell lines that express both SALL4A and SALL4B (Kong et al, 2021, Vu, Kumari et al, 2023. To target SALL4+ cancer cells, we need to degrade both isoforms, therefore, we focused on targeting ZFC4, which is shared by both SALL4A and SALL4B.…”