A Runaway PRH/HHEX-Notch3-Positive Feedback Loop Drives Cholangiocarcinoma and Determines Response to CDK4/6 Inhibition

Research output: Contribution to journalArticle

Authors

  • Ka Ying Lee
  • Danielle J Clark
  • Nikki Lau
  • Jomnarong Lertsuwan
  • Jutamaad Satayavivad
  • Sebastian Oltean
  • Kevin Gaston

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.

Details

Original languageEnglish
Pages (from-to)757-770
JournalCancer Research
Volume80
Issue number4
Early online date16 Dec 2019
Publication statusPublished - 15 Feb 2020

Keywords

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