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

Abstract

Aberrant Notch and Wnt signaling are known drivers of cholangiocarcinoma (CCA), but the underlying factors that initiate and maintain these pathways are not known. Here, we show that the proline-rich homeodomain protein/hematopoietically expressed homeobox (PRH/HHEX) transcription factor forms a positive transcriptional feedback loop with Notch3 that is critical in CCA. PRH/HHEX expression is elevated in CCA, and depletion of PRH reduces CCA tumor growth in a xenograft model. Overexpression of PRH in primary human biliary epithelial cells is sufficient to increase cell proliferation and produce an invasive phenotype. Interrogation of the gene networks regulated by PRH and Notch3 reveals that unlike Notch3, PRH directly activates canonical Wnt signaling. These data indicate that hyperactivation of Notch and Wnt signaling 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. SIGNIFICANCE: The PRH/HHEX transcription factor is an oncogenic driver in cholangiocarcinoma that confers sensitivity to CDK4/6 inhibitors.

• Authors: Philip Kitchen, Ka Ying Lee, Danielle Clark, Nikki Lau, Jomnarong Lertsuwan, Anyaporn Sawasdichai, Jutamaad Satayavivad, Sebastian Oltean, Simon Afford, Kevin Gaston, Padma-Sheela Jayaraman
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 4 Pg. 757-770 (02 15 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 31843982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• HHEX protein, human
• Homeodomain Proteins
• NOTCH3 protein, human
• Piperazines
• Pyridines
• Receptor, Notch3
• Transcription Factors
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• palbociclib

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Bile Duct Neoplasms (drug therapy, genetics, pathology)
• Bile Ducts, Intrahepatic (cytology, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cholangiocarcinoma (drug therapy, genetics, pathology)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Drug Resistance, Neoplasm (genetics)
• Epithelial Cells
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Gene Regulatory Networks
• Homeodomain Proteins (genetics, metabolism)
• Humans
• K562 Cells
• Male
• Mice
• Mutation
• Neoplasm Invasiveness (genetics)
• Piperazines (pharmacology, therapeutic use)
• Primary Cell Culture
• Promoter Regions, Genetic
• Pyridines (pharmacology, therapeutic use)
• RNA-Seq
• Receptor, Notch3 (metabolism)
• Transcription Factors (genetics, metabolism)
• Wnt Signaling Pathway (genetics)
• Xenograft Model Antitumor Assays