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

Publication ,  Journal Article
Kovach, AR; Oristian, KM; Kirsch, DG; Bentley, RC; Cheng, C; Chen, X; Chen, P-H; Chi, J-TA; Linardic, CM
Published in: Mol Oncol
October 2022

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.

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Published In

Mol Oncol

DOI

EISSN

1878-0261

Publication Date

October 2022

Volume

16

Issue

20

Start / End Page

3587 / 3605

Location

United States

Related Subject Headings

  • Transcription Factor HES-1
  • Rhabdomyosarcoma
  • RNA, Small Interfering
  • Proteomics
  • Oncology & Carcinogenesis
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Cyclin-Dependent Kinase Inhibitor p57
  • Cell Proliferation
  • Cell Line, Tumor
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kovach, A. R., Oristian, K. M., Kirsch, D. G., Bentley, R. C., Cheng, C., Chen, X., … Linardic, C. M. (2022). Identification and targeting of a HES1-YAP1-CDKN1C functional interaction in fusion-negative rhabdomyosarcoma. Mol Oncol, 16(20), 3587–3605. https://doi.org/10.1002/1878-0261.13304
Kovach, Alexander R., Kristianne M. Oristian, David G. Kirsch, Rex C. Bentley, Changde Cheng, Xiang Chen, Po-Han Chen, Jen-Tsan Ashley Chi, and Corinne M. Linardic. “Identification and targeting of a HES1-YAP1-CDKN1C functional interaction in fusion-negative rhabdomyosarcoma.Mol Oncol 16, no. 20 (October 2022): 3587–3605. https://doi.org/10.1002/1878-0261.13304.
Kovach AR, Oristian KM, Kirsch DG, Bentley RC, Cheng C, Chen X, et al. Identification and targeting of a HES1-YAP1-CDKN1C functional interaction in fusion-negative rhabdomyosarcoma. Mol Oncol. 2022 Oct;16(20):3587–605.
Kovach, Alexander R., et al. “Identification and targeting of a HES1-YAP1-CDKN1C functional interaction in fusion-negative rhabdomyosarcoma.Mol Oncol, vol. 16, no. 20, Oct. 2022, pp. 3587–605. Pubmed, doi:10.1002/1878-0261.13304.
Kovach AR, Oristian KM, Kirsch DG, Bentley RC, Cheng C, Chen X, Chen P-H, Chi J-TA, Linardic CM. Identification and targeting of a HES1-YAP1-CDKN1C functional interaction in fusion-negative rhabdomyosarcoma. Mol Oncol. 2022 Oct;16(20):3587–3605.

Published In

Mol Oncol

DOI

EISSN

1878-0261

Publication Date

October 2022

Volume

16

Issue

20

Start / End Page

3587 / 3605

Location

United States

Related Subject Headings

  • Transcription Factor HES-1
  • Rhabdomyosarcoma
  • RNA, Small Interfering
  • Proteomics
  • Oncology & Carcinogenesis
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Cyclin-Dependent Kinase Inhibitor p57
  • Cell Proliferation
  • Cell Line, Tumor