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

Kim Anh L VuKalpana KumariBee Hui LiuChong GaoFeng LiJing Ping TangDanilo MaddaloDouglas S AuldDominick E CasalenaXi TianMiao LiuMahmoud Adel BassalShiva MoeinViktoriia IakovlevaJustin L TanAlicia J SteinQiling ZhouPatrick D FischerLogan H SiguaJun QiHaribabu ArthanariDaniel Geoffrey TenenLi Chai
Published in: bioRxiv : the preprint server for biology (2023)
Oncofetal transcription factor SALL4 is essential for cancer cell survival. 1-5 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.
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