SHEELA JAYARAMAN Sheela.Jayaraman@nottingham.ac.uk
Professor of Cancer Biology and Gene Regulation
A runaway PRH/HHEX-Notch3 positive feedback loop drives cholangiocarcinoma and determines response to CDK4/6 inhibition
Jayaraman, Padma-Sheela; Kitchen, Philip; Gaston, Kevin; Lee, Ka Ying; Afford, Simon; Clark, Danielle; Oltean, Sebastian; Lau, Nikki; Satayavivad, Jutamaad; Lertsuwan, Jomnarong; Sawasdichai, Anyaporn
Authors
Philip Kitchen
Professor KEVIN GASTON Kevin.Gaston@nottingham.ac.uk
Professor of Cancer Studies
Ka Ying Lee
Simon Afford
Danielle Clark
Sebastian Oltean
Nikki Lau
Jutamaad Satayavivad
Jomnarong Lertsuwan
Anyaporn Sawasdichai
Abstract
Aberrant Notch and Wnt signalling are known drivers of cholangiocarcinoma (CCA) but the underlying factors that initiate and maintain these pathways are not known. Here we show that the PRH/HHEX transcription factor forms a positive transcriptional feedback loop with Notch3 that is critical in CCA. PRH/HHEX expression was elevated in CCA and depletion of PRH reduced CCA tumour growth in a xenograft model. Overexpression of PRH in primary human biliary epithelial cells was sufficient to increase cell proliferation and produce an invasive phenotype. Interrogation of the gene networks regulated by PRH and Notch3 revealed that unlike Notch3, PRH directly activated canonical Wnt signalling. These data indicate that hyperactivation of Notch and Wnt signalling is independent of the underlying mutational landscape and has a common origin in dysregulation of PRH. Moreover, they suggest new therapeutic options based on the dependence of specific Wnt, Notch, and CDK4/6 inhibitors on PRH activity.
Citation
Jayaraman, P.-S., Kitchen, P., Gaston, K., Lee, K. Y., Afford, S., Clark, D., …Sawasdichai, A. (2020). A runaway PRH/HHEX-Notch3 positive feedback loop drives cholangiocarcinoma and determines response to CDK4/6 inhibition. Cancer Research, 80(4), 757-770. https://doi.org/10.1158/0008-5472.can-19-0942
Journal Article Type | Article |
---|---|
Acceptance Date | Dec 10, 2019 |
Online Publication Date | Dec 16, 2019 |
Publication Date | 2020-02 |
Deposit Date | Jan 9, 2020 |
Publicly Available Date | Dec 17, 2020 |
Journal | Cancer Research |
Print ISSN | 0008-5472 |
Electronic ISSN | 1538-7445 |
Publisher | American Association for Cancer Research |
Peer Reviewed | Peer Reviewed |
Volume | 80 |
Issue | 4 |
Pages | 757-770 |
DOI | https://doi.org/10.1158/0008-5472.can-19-0942 |
Keywords | Cancer Research; Oncology |
Public URL | https://nottingham-repository.worktribe.com/output/3694654 |
Publisher URL | https://cancerres.aacrjournals.org/content/80/4/757 |
Files
0008-5472.CAN-19-0942.full
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