Crosstalk between Hedgehog pathway and the glucocorticoid receptor pathway as a basis for combination therapy in T-cell acute lymphoblastic leukemia

Abstract

Notwithstanding intensified therapy, a considerable fraction of T-cell acute lymphoblastic leukemia (T-ALL) patients face a dismal prognosis due to primary resistance to treatment and relapse, raising the need for more efficient and targeted therapies. Hedgehog (HH) signaling is a major developmental pathway frequently deregulated in cancer, for which a role in T-ALL is emerging. Mounting evidence suggests that ligand-independent activation of HH pathway occurs in cancer including T-ALL, emphasizing the necessity of dissecting the complex interplay between HH and other signaling pathways regulating activation. In this work, we present a therapeutically relevant crosstalk between HH signaling and the glucocorticoid receptor (NR3C1) pathway acting at the level of GLI1 transcription factor. GLI inhibitor GANT61 and dexamethasone were shown to exert a synergistic anti-leukemic effect in vitro in T-ALL cell lines and patient-derived xenografts. Mechanistically, dexamethasone-activated NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase and HDAC1 deacetylase. Increased GLI1 acetylation was associated with compromised transcriptional activity and reduced protein stability. In summary, our study identifies a novel crosstalk between GLI1 and NR3C1 signaling pathway which could be exploited in HH-dependent malignancies to increase therapeutic efficacy.

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Fig. 1: NOTCH1 signaling and the glucocorticoid receptor pathways modulate sensitivity to GLI1 inhibitor GANT61 in T-ALL cells.
Fig. 2: GANT61 and dexa synergistically reduce cell viability in vitro in T-ALL cell lines and PDX samples.
Fig. 3: NR3C1 signaling negatively affects GLI1 function.
Fig. 4: NR3C1 interacts with GLI1 and modulates the recruitment of mediators of GLI1 acetylation/deacetylation.
Fig. 5: Dexa accelerates GLI1 turnover via proteasome-dependent degradation.

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Acknowledgements

We are grateful to Prof Warren Pear (University of Pennsylvania, Philadelphia, U.S.A) for the MigR1vector, Prof Raphael Kopan (Washington University, St. Louis, U.S.A.) for MigR1 vectors expressing ΔE-NOTCH1 mutant allele, Prof J. Aster (Brigham and Women’s Hospital, Harvard Medical School, Boston, U.S.A.) for the MigR1 HD-ΔPEST (NOTCH1 L1601P-ΔPEST) vector. Histidine-HA-Ubiquitin vector was a kind gift from Richard Baer (Columbia University). We thank Sonia Minuzzo and Marica Pinazza for providing T-ALL xenografts, Elena Laura Mazzoldi for cell sorting, Elena Masiero for technical assistance. We are grateful to Pieter Van Vlierberghe and Giorgio Arrigoni for reagents and suggestions.

Funding

This work was supported by the Italian Foundation for Cancer Research (Fondazione AIRC) grants to EP (IG2018#22233); Progetto di Ricerca di Ateneo (SID19_01; Università di Padova) to EP. Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) Ex 60% to EP; Istituto Oncologico Veneto 5 × 1000 fund to EP.

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Correspondence to Erich Piovan.

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Bongiovanni, D., Tosello, V., Saccomani, V. et al. Crosstalk between Hedgehog pathway and the glucocorticoid receptor pathway as a basis for combination therapy in T-cell acute lymphoblastic leukemia. Oncogene (2020). https://doi.org/10.1038/s41388-020-01453-2

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