FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

• Published in: Journal of hepatology Vol. 75; no. 2; pp. 363 - 376
• Main Authors: Vallejo, Adrián, Erice, Oihane, Entrialgo-Cadierno, Rodrigo, Feliu, Iker, Guruceaga, Elizabeth, Perugorria, Maria J., Olaizola, Paula, Muggli, Alexandra, Macaya, Irati, O’Dell, Michael, Ruiz-Fernandez de Cordoba, Borja, Ortiz-Espinosa, Sergio, Hezel, Aram F., Arozarena, Imanol, Lecanda, Fernando, Avila, Matias A., Fernandez-Barrena, Maite G., Evert, Matthias, Ponz-Sarvise, Mariano, Calvisi, Diego F., Banales, Jesus M., Vicent, Silve
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-08-2021; Elsevier Science Ltd
• Subjects: Aged; Bile ducts; Biliary tract; Cell cycle; Cell proliferation; Cholangiocarcinoma; Cholangiocarcinoma - diagnosis; Cholangiocarcinoma - etiology; Cholangiocarcinoma - genetics; Chromatin; Epigenetics; Female; FOSL1; Genetic engineering; genetics; Humans; Hydroxymethylglutaryl-CoA Synthase - drug effects; Hydroxymethylglutaryl-CoA Synthase - genetics; Immunoprecipitation; Male; Middle Aged; Molecular modelling; Proto-Oncogene Proteins c-fos - adverse effects; Proto-Oncogene Proteins c-fos - genetics; Signal transduction; targeted therapies; Transcription factors; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; Tumors; Xenografts; FOSL1; genetics; targeted therapies; transcription factors; cholangiocarcinoma
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2021.03.028

Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA.
FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Follow-up RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition.
An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss.
Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies.
Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.
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•The transcription factor FOSL1 is upregulated in human and mouse CCA, and is independently associated with patient survival.•Genetic FOSL1 inhibition impairs cell proliferation and cell cycle progression in vitro, and tumor initiation and maintenance in vivo.•The mevalonate pathway gene HMGCS1 is upregulated in human and mouse CCA, and its expression is controlled by direct FOSL1 promoter binding.•Genetic HMGCS1 abrogation or pharmacological blockade with mTOR inhibitors phenocopies loss of FOSL1.