Wu, XiaofengZhang, Li-shuToombs, JasonKuo, Yi-ChunPiazza, John TylerTuladhar, RubinaBarrett, QuinnFan, Chih-weiZhang, XuewuWalensky, LorenKool, MarcelCheng, Steven Y.Brekken, RolfOpferman, Joseph T.Green, Douglas R.Moldoveanu, TudorLum, Lawrence2018-04-192017Wu, X., L. Zhang, J. Toombs, Y. Kuo, J. T. Piazza, R. Tuladhar, Q. Barrett, et al. 2017. “Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumor suppressor.” Nature cell biology 19 (10): 1226-1236. doi:10.1038/ncb3616. http://dx.doi.org/10.1038/ncb3616.http://nrs.harvard.edu/urn-3:HUL.InstRepos:35981959SUMMARY Direct interactions between pro- and anti-apoptotic BCL-2 family members form the basis of cell death decision-making at the outer mitochondrial membrane (OMM). Here we report that three antiapoptotic BCL-2 proteins (MCL-1, BCL-2, and BCL-XL) found untethered from the OMM function as transcriptional regulators of a prosurvival and growth program. Antiapoptotic BCL-2 proteins engage a BCL-2 homology (BH) domain sequence found in Suppressor of Fused (SUFU), a tumor suppressor and antagonist of the GLI DNA binding proteins. BCL-2 proteins directly promote SUFU turnover, inhibit SUFU-GLI interaction, and induce the expression of the GLI target genes BCL-2, MCL-1, and BCL-XL. Antiapoptotic BCL-2 protein/SUFU feedforward signaling promotes cancer cell survival and growth and can be disabled with BH3 mimetics – small molecules that target antiapoptotic BCL-2 proteins. Our findings delineate a chemical strategy for countering drug resistance in GLI-associated tumors and reveal unanticipated functions for BCL-2 proteins as transcriptional regulators.en-USJournal Article2018-04-1910.1038/ncb3616