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Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer

Nature Medicine volume 21, pages 457–466 (2015)Cite this article

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Abstract

A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)—a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive—inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML–RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.

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Figure 1: Mechanism-based screening identifies ATRA as a submicromolar Pin1 inhibitor that binds to the Pin1 active site.
Figure 2: ATRA causes Pin1 degradation and inhibits its oncogenic function in cells.
Figure 3: Pin1 is a critical target for ATRA to induce PML–RAR-α degradation and inhibit proliferation in APL cells.
Figure 4: Inhibition of Pin1 by ATRA or other compounds causes PML–RAR-α degradation and treats APL in cell and mouse models and human subjects.
Figure 5: ATRA ablates active Pin1 and thereby turns off oncogenes and turns on tumor suppressors in breast cancer.
Figure 6: ATRA exerts potent anticancer activity against TNBC in vivo by ablating Pin1 and thereby blocking multiple cancer pathways simultaneously.

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References

  1. Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  2. Lu, K.P. & Zhou, X.Z. The prolyl isomerase Pin1: a pivotal new twist in phosphorylation signalling and human disease. Nat. Rev. Mol. Cell Biol. 8, 904–916 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Lu, Z. & Hunter, T. Pin1 and cancer. Cell Res. 24, 1033–1049 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lu, K.P., Finn, G., Lee, T.H. & Nicholson, L.K. Prolyl cis-trans isomerization as a molecular timer. Nat. Chem. Biol. 3, 619–629 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Yaffe, M.B. et al. Sequence-specific and phosphorylation-dependent proline isomerization: A potential mitotic regulatory mechanism. Science 278, 1957–1960 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Nakamura, K. et al. Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease. Cell 149, 232–244 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee, T.H. et al. Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol. Cell 42, 147–159 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li, Q. et al. The rs2233678 polymorphism in PIN1 promoter region reduced cancer risk: a meta-analysis. PLoS ONE 8, e68148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wulf, G., Garg, P., Liou, Y.C., Iglehart, D. & Lu, K.P. Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO J. 23, 3397–3407 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Suizu, F., Ryo, A., Wulf, G., Lim, J. & Lu, K.P. Pin1 regulates centrosome duplication and its overexpression induces centrosome amplification, chromosome instability and oncogenesis. Mol. Cell. Biol. 26, 1463–1479 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wulf, G.M. et al. Pin1 is overexpressed in breast cancer and potentiates the transcriptional activity of phosphorylated c-Jun towards the cyclin D1 gene. EMBO J. 20, 3459–3472 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liou, Y.C. et al. Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc. Natl. Acad. Sci. USA 99, 1335–1340 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ryo, A. et al. Regulation of NF-κB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol. Cell 12, 1413–1426 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Lam, P.B. et al. Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability. Mol. Cancer 7, 91 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Stanya, K.J., Liu, Y., Means, A.R. & Kao, H.Y. Cdk2 and Pin1 negatively regulate the transcriptional co-repressor SMRT. J. Cell Biol. 183, 49–61 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liao, Y. et al. Peptidyl-prolyl cis/trans isomerase Pin1 is critical for the regulation of PKB/Akt stability and activation phosphorylation. Oncogene 28, 2436–2445 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nakano, A. et al. Pin1 downregulates TGF-β signaling by inducing degradation of Smad proteins. J. Biol. Chem. 284, 6109–6115 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Rajbhandari, P. et al. Regulation of estrogen receptor-α N-terminus conformation and function by peptidyl prolyl isomerase Pin1. Mol. Cell. Biol. 32, 445–457 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang, W. et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat. Cell Biol. 14, 1295–1304 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Min, S.H. et al. Negative regulation of the stability and tumor suppressor function of Fbw7 by the pin1 prolyl isomerase. Mol. Cell 46, 771–783 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Luo, M.L. et al. Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer. Cancer Res. 74, 3603–3616 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Luo, M.L. et al. The Rab2A GTPase is a breast cancer stem-promoting gene that enhances tumorigenesis via activating Erk signaling. Cell Reports (in the press) (2015).

  23. Rustighi, A. et al. Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast. EMBO Mol. Med. 6, 99–119 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Lu, K.P. Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics. Cancer Cell 4, 175–180 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Fujimori, F., Takahashi, K., Uchida, C. & Uchida, T. Mice lacking Pin1 develop normally, but are defective in entering cell cycle from G(0) arrest. Biochem. Biophys. Res. Commun. 265, 658–663 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Liou, Y.-C. et al. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424, 556–561 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Moore, J.D. & Potter, A. Pin1 inhibitors: pitfalls, progress and cellular pharmacology. Bioorg. Med. Chem. Lett. 23, 4283–4291 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Bialik, S. & Kimchi, A. The death-associated protein kinases: structure, function, and beyond. Annu. Rev. Biochem. 75, 189–210 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, Y. et al. Structural basis for high-affinity peptide inhibition of human Pin1. ACS Chem. Biol. 2, 320–328 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Auld, D.S. et al. Receptor binding assays for HTS and drug discovery. in Assay Guidance Manual (eds. Sittampalam, G.S., et al.) (Eli Lilly & Company and the National Center for Advancing Translational Sciences, 2004).

  31. Chen, H. & Juchau, M.R. Recombinant human glutathione S-transferases catalyse enzymic isomerization of 13-cis-retinoic acid to all-trans-retinoic acid in vitro. Biochem. J. 336, 223–226 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bernstein, P.S., Choi, S.Y., Ho, Y.C. & Rando, R.R. Photoaffinity labeling of retinoic acid-binding proteins. Proc. Natl. Acad. Sci. USA 92, 654–658 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moon, R.C. et al. N-(4-Hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat. Cancer Res. 39, 1339–1346 (1979).

    CAS  PubMed  Google Scholar 

  34. Boehm, M.F. et al. Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. J. Med. Chem. 38, 3146–3155 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Connolly, R.M., Nguyen, N.K. & Sukumar, S. Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment. Clin. Cancer Res. 19, 1651–1659 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang, M.E. et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72, 567–572 (1988).

    Article  CAS  PubMed  Google Scholar 

  37. de Thé, H. & Chen, Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat. Rev. Cancer 10, 775–783 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Sanz, M.A. & Lo-Coco, F. Modern approaches to treating acute promyelocytic leukemia. J. Clin. Oncol. 29, 495–503 (2011).

    Article  PubMed  Google Scholar 

  39. Nasr, R. et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat. Med. 14, 1333–1342 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Ablain, J. et al. Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies. J. Exp. Med. 210, 647–653 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Langenfeld, J., Kiyokawa, H., Sekula, D., Boyle, J. & Dmitrovsky, E. Posttranslational regulation of cyclin D1 by retinoic acid: a chemoprevention mechanism. Proc. Natl. Acad. Sci. USA 94, 12070–12074 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tsai, Y.C. et al. Effects of all-trans retinoic acid on Th1- and Th2-related chemokines production in monocytes. Inflammation 31, 428–433 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Sheng, N. et al. Retinoic acid regulates bone morphogenic protein signal duration by promoting the degradation of phosphorylated Smad1. Proc. Natl. Acad. Sci. USA 107, 18886–18891 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lanotte, M. et al. NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3). Blood 77, 1080–1086 (1991).

    Article  CAS  PubMed  Google Scholar 

  45. Brondani, V., Schefer, Q., Hamy, F. & Klimkait, T. The peptidyl-prolyl isomerase Pin1 regulates phospho-Ser77 retinoic acid receptor alpha stability. Biochem. Biophys. Res. Commun. 328, 6–13 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Gausdal, G. et al. Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis. Cell Death Dis. 4, e516 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Uchida, T. et al. Pin1 and Par14 peptidyl prolyl isomerase inhibitors block cell proliferation. Chem. Biol. 10, 15–24 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Urusova, D.V. et al. Epigallocatechin-gallate suppresses tumorigenesis by directly targeting Pin1. Cancer Prev. Res. (Phila.) 4, 1366–1377 (2011).

    Article  CAS  PubMed Central  Google Scholar 

  49. Hennig, L. et al. Selective inactivation of parvulin-like peptidyl-prolyl cis/trans isomerases by juglone. Biochemistry 37, 5953–5960 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. He, L.Z. et al. Acute leukemia with promyelocytic features in PML/RARα transgenic mice. Proc. Natl. Acad. Sci. USA 94, 5302–5307 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Song, M.S. et al. The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network. Nature 455, 813–817 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Budd, G.T. et al. Phase I/II trial of all-trans retinoic acid and tamoxifen in patients with advanced breast cancer. Clin. Cancer Res. 4, 635–642 (1998).

    CAS  PubMed  Google Scholar 

  53. Muindi, J. et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid “resistance” in patients with acute promyelocytic leukemia. Blood 79, 299–303 (1992).

    Article  CAS  PubMed  Google Scholar 

  54. Kogan, S.C., Hong, S.H., Shultz, D.B., Privalsky, M.L. & Bishop, J.M. Leukemia initiated by PMLRARα: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable. Blood 95, 1541–1550 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Arrieta, O. et al. Randomized phase II trial of all-trans-retinoic acid with chemotherapy based on paclitaxel and cisplatin as first-line treatment in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 3463–3471 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Ramlau, R. et al. Randomized phase III trial comparing bexarotene (L1069–49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J. Clin. Oncol. 26, 1886–1892 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Decensi, A. et al. Randomized double-blind 2 × 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women. J. Clin. Oncol. 27, 3749–3756 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Muindi, J.R. et al. Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia. Cancer Res. 52, 2138–2142 (1992).

    CAS  PubMed  Google Scholar 

  59. Gianni, M. et al. Inhibition of the peptidyl-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic acid via stabilization of RARα and PML-RARα. Cancer Res. 69, 1016–1026 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Jain, P. et al. Single-agent liposomal all-trans-retinoic acid as initial therapy for acute promyelocytic leukemia: 13-year follow-up data. Clin. Lymphoma, Myeloma Leuk. 14, e47–e49 (2014).

    Article  Google Scholar 

  61. Lu, P.J., Zhou, X.Z., Liou, Y.C., Noel, J.P. & Lu, K.P. Critical role of WW domain phosphorylation in regulating its phosphoserine-binding activity and the Pin1 function. J. Biol. Chem. 277, 2381–2384 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Wildemann, D. et al. Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pin1 from combinatorial peptide libraries. J. Med. Chem. 49, 2147–2150 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Ryo, A., Nakamura, N., Wulf, G., Liou, Y.C. & Lu, K.P. Pin1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC. Nat. Cell Biol. 3, 793–801 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D. Biol. Crystallogr. 50, 760–763 (1994).

  66. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Laskowski, R.A., Moss, D.S. & Thornton, J.M. Main-chain bond lengths and bond angles in protein structures. J. Mol. Biol. 231, 1049–1067 (1993).

    Article  CAS  PubMed  Google Scholar 

  69. Chen, V.B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Shultz, L.D. et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. dos Santos, G.A. et al. α-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo. Leukemia 26, 451–460 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Lo-Coco, F. et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369, 111–121 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Rego, E.M. et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood 121, 1935–1943 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank W.G. Kaelin Jr., N. Gray, J. Clardy and A. Chakraborty for constructive advice; and H. de Thé (INSERM) for RAR-α, RAR-β, and RAR-γ triple-KO MEFs originally generated by P.A. Chambon (Université de Strasbourg); C. Ng for assistance with immunostaining and T. Garvey for editing the manuscript. S.W. is a recipient of a Susan G. Komen for the Cure postdoctoral fellowship (KG111233). The work is supported by grants from the US National Institutes of Health (R01CA167677, R03DA031663 and R01HL111430 to K.P.L.).

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  1. Shugeng Cao

    Present address: Present address: Department of Natural Products and Experimental Therapeutics, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.,

Authors and Affiliations

  1. Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA

    Shuo Wei, Shingo Kozono, Morris Nechama, Manli Luo, Yandan Yao, Asami Kondo, Chun-Hau Chen, Xiao Zhen Zhou & Kun Ping Lu

  2. Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.,

    Shuo Wei, Shingo Kozono, Lev Kats, Morris Nechama, Jlenia Guarnerio, Manli Luo, Yandan Yao, Asami Kondo, Hai Hu, Markus Reschke, Chun-Hau Chen, Lewis C Cantley, Pier Paolo Pandolfi, Xiao Zhen Zhou & Kun Ping Lu

  3. Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

    Shuo Wei, Shingo Kozono, Lev Kats, Morris Nechama, Jlenia Guarnerio, Manli Luo, Yandan Yao, Asami Kondo, Hai Hu, Markus Reschke, Chun-Hau Chen, Lewis C Cantley, Pier Paolo Pandolfi, Xiao Zhen Zhou & Kun Ping Lu

  4. Department of Pathology, BIDMC, Harvard Medical School, Boston, Massachusetts, USA

    Lev Kats, Jlenia Guarnerio, Markus Reschke & Pier Paolo Pandolfi

  5. Department of Molecular Biosciences, University of Texas, Austin, Texas, USA

    Wenzong Li & Yan Zhang

  6. Division of Gerontology, Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA

    Mi-Hyeon You & Tae Ho Lee

  7. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Gunes Bozkurt, Shugeng Cao & Hao Wu

  8. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA

    Nathan J Moerke & Lewis C Cantley

  9. Department of Internal Medicine, University of São Paulo, Ribeirão Preto, Brazil

    Eduardo M Rego

  10. Department of Biomedicine and Prevention, Tor Vergata University and Santa Lucia Foundation, Rome, Italy

    Francesco Lo-Coco

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Contributions

S.W. designed the studies, performed the experiments, interpreted the data, and wrote the manuscript; S.K. helped characterize ATRA binding to and inhibition of Pin1; L.K., J.G. and M.R. helped design and conduct APL-related experiments; W.L. and Y.Z. determined the Pin1–ATRA co-crystal structure; M.N., M.L., Y.Y., A.K., H.H., and C.H.C. provided various technical assistances; M.-H.Y and T.H.L. performed Pin1 and DAPK1 immunostaining; G.B. and H.W. helped analyze Pin1 and ATRA binding; N.J.M. and S.C. provided advice on the FP-HTS screen; E.M.R. and F.L.-C. provided human APL samples; L.C.C. advised the project; P.P.P. advised the project, interpreted the data and reviewed the manuscript; X.Z.Z. developed the original Pin1 FP-HTS and worked with S.W. to identify ATRA; X.Z.Z. and K.P.L. conceived and supervised the project, designed the studies, interpreted the data, and wrote the manuscript.

Corresponding authors

Correspondence to Xiao Zhen Zhou or Kun Ping Lu.

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Competing interests

K.P.L. and X.Z.Z. are the inventors of Pin1 inhibition technology, which was licensed by BIDMC to Pinteon Therapeutics. K.P.L. and X.Z.Z. own equity in and consult for Pinteon. K.P.L. also serves on its board of directors. Their interests were reviewed and are managed by BIDMC in accordance with its conflict of interest policy.

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Wei, S., Kozono, S., Kats, L. et al. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med 21, 457–466 (2015). https://doi.org/10.1038/nm.3839

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