Identification and targeting of a HES1-YAP1-CDKN1C functional interaction in fusion-negative rhabdomyosarcoma.

Autor: Kovach AR; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Oristian KM; Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA.; Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA., Kirsch DG; Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA.; Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA., Bentley RC; Department of Pathology, Duke University, Durham, NC, USA., Cheng C; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Chen X; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Chen PH; Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC, USA., Chi JA; Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC, USA., Linardic CM; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.; Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2022 Oct; Vol. 16 (20), pp. 3587-3605. Date of Electronic Publication: 2022 Aug 29.
DOI: 10.1002/1878-0261.13304
Abstrakt: Rhabdomyosarcoma (RMS), a cancer characterized by features of skeletal muscle, is the most common soft-tissue sarcoma of childhood. With 5-year survival rates among high-risk groups at < 30%, new therapeutics are desperately needed. Previously, using a myoblast-based model of fusion-negative RMS (FN-RMS), we found that expression of the Hippo pathway effector transcriptional coactivator YAP1 (YAP1) permitted senescence bypass and subsequent transformation to malignant cells, mimicking FN-RMS. We also found that YAP1 engages in a positive feedback loop with Notch signaling to promote FN-RMS tumorigenesis. However, we could not identify an immediate downstream impact of this Hippo-Notch relationship. Here, we identify a HES1-YAP1-CDKN1C functional interaction, and show that knockdown of the Notch effector HES1 (Hes family BHLH transcription factor 1) impairs growth of multiple FN-RMS cell lines, with knockdown resulting in decreased YAP1 and increased CDKN1C expression. In silico mining of published proteomic and transcriptomic profiles of human RMS patient-derived xenografts revealed the same pattern of HES1-YAP1-CDKN1C expression. Treatment of FN-RMS cells in vitro with the recently described HES1 small-molecule inhibitor, JI130, limited FN-RMS cell growth. Inhibition of HES1 in vivo via conditional expression of a HES1-directed shRNA or JI130 dosing impaired FN-RMS tumor xenograft growth. Lastly, targeted transcriptomic profiling of FN-RMS xenografts in the context of HES1 suppression identified associations between HES1 and RAS-MAPK signaling. In summary, these in vitro and in vivo preclinical studies support the further investigation of HES1 as a therapeutic target in FN-RMS.
(© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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