Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor PMID: 28945232

ADC Targets in Oncology

2026-04-10

Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor

Nat Cell Biol. 2017 Oct;19(10):1226-1236. doi: 10.1038/ncb3616.

Xiaofeng Wu ¹ , Li-Shu Zhang ¹ , Jason Toombs ² ³ , Yi-Chun Kuo ³ ⁴ , John Tyler Piazza ¹ , Rubina Tuladhar ¹ , Quinn Barrett ¹ , Chih-Wei Fan ¹ , Xuewu Zhang ³ ⁴ , Loren D Walensky ⁵ ⁶ , Marcel Kool ⁷ ⁸ , Steven Y Cheng ⁹ ¹⁰ , Rolf Brekken ² ³ , Joseph T Opferman ¹¹ , Douglas R Green ¹² , Tudor Moldoveanu ¹³ ¹⁴ , Lawrence Lum ¹

Affiliations

1. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
2. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
3. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
4. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
5. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
6. Department of Pediatrics, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
7. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
8. German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany.
9. Department of Developmental Genetics, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.
10. Center for Regenerative Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.
11. Cell &Molecular Biology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA.
12. Immunology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA.
13. Structural Biology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA.
14. Chemical Biology and Therapeutics Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA.

Abstract

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 anti-apoptotic 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. Anti-apoptotic Bcl-2 proteins engage a Bcl-2 homology (BH) domain sequence found in SUFU (suppressor of fused), a tumour 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. Anti-apoptotic Bcl-2 protein/SUFU feedforward signalling promotes Cancer cell survival and growth, and can be disabled with BH3 mimetics-small molecules that target anti-apoptotic Bcl-2 proteins. Our findings delineate a chemical strategy for countering drug resistance in GLI-associated tumours and reveal unanticipated functions for Bcl-2 proteins as transcriptional regulators.