Pathogenic role and therapeutic targeting of BAP1 loss in tumor metastasis
General Genetics and Functional Genome Biology
Biochemistry
Bioinformatics and Theoretical Biology
Hematology, Oncology
Reproductive Medicine, Urology
Final Report Abstract
We previously classified renal cell carcinoma based on inactivating mutations in BAP1 and another epigenetic modifier, PBRM1. While BAP1 inactivation is associated with aggressive tumors, metastasis, and poor patient survival, PBRM1 loss is associated with good prognosis and a positive response to immune checkpoint inhibitors. However, there are no specific treatments for tumors with mutations in BAP1. We hypothesized that BAP1 regulates the expression of a miRNA cluster involved in metastasis. By generating truncating deletions in its promoter region, we identified the minimum area of regulation by BAP1. Unfortunately, proteomics analyses showed that BAP1 does not bind to the promoter region of the miRNA cluster. As an alternative, bioinformatics analyses revealed that E2F1 is the top candidate among the transcription factors that bind to the minimal region of regulation of the miRNA cluster by BAP1. Further experiments showed that E2F1 is necessary for the induction of the expression of the miRNA by BAP1 loss. A better level of overexpression of E2F1 was required not to overload the cells and to test its sufficiency appropriately. We compared several miRNA inhibitors and found that Exiqon miRNA inhibitors outperformed mirVana miRNA inhibitors in sensitivity and specificity of the miRNAs in vitro using gymnosis, which consist in adding directly the miRNA inhibitors to the medium without any carrier or transfection reagent. Unfortunately, the Nature paper we used as reference for the in vivo studies of the miRNA inhibitors was recently retracted. Therefore, we decided not to continue with this specific aim. In addition, we analyzed the genetic vulnerabilities of BAP1-mutated cancers using a large-scale RNA interference screen and found that a histone deacetylase is synthetically lethal with BAP1 loss. We validated this in vitro using several cell lines of renal cell carcinoma and cholangiocarcinoma and in vivo in mice. This study could lead to new therapies for the treatment of patients with lethal tumors with BAP1 mutations and starting clinical trials soon.
Publications
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A BAP1 synonymous mutation results in exon skipping, loss of function and worse patient prognosis. iScience, 24(3), 102173.
Niersch, Jennifer; Vega-Rubín-de-Celis, Silvia; Bazarna, Anna; Mergener, Svenja; Jendrossek, Verena; Siveke, Jens T. & Peña-Llopis, Samuel
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Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma. International Journal of Molecular Sciences, 22(13), 6727.
Mergener, Svenja; Siveke, Jens T. & Peña-Llopis, Samuel
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A Dual HiBiT-GFP-LC3 Lentiviral Reporter for Autophagy Flux Assessment. Methods in Molecular Biology, 75-98. Springer US.
Will, Rainer; Bauer, Katja; Kudla, Matthias; Montero-Vergara, Jetsy; Wiemann, Stefan; Jendrossek, Verena; Peña-Llopis, Samuel & Vega-Rubín-de-Celis, Silvia
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Nintedanib and Dasatinib Treatments Induce Protective Autophagy as a Potential Resistance Mechanism in MPM Cells. Frontiers in Cell and Developmental Biology, 10.
Hegedüs, Luca; Szücs, Kata D.; Kudla, Matthias; Heidenreich, Julian; Jendrossek, Verena; Peña-Llopis, Samuel; Garay, Tamas; Czirok, Andras; Aigner, Clemens; Plönes, Till; Vega-Rubin-de-Celis, Silvia & Hegedüs, Balazs
