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A long non-coding RNA links calreticulin-mediated immunogenic cell removal to RB1 transcription

Oncogene volume 34, pages 5046–5054 (2015)Cite this article

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Abstract

A subset of promoters bidirectionally expresses long non-coding RNAs (ncRNAs) of unknown function and protein-coding genes (PCGs) in parallel. Here, we define a set of 1107 highly conserved human bidirectional promoters that mediate the linked expression of long ncRNAs and PCGs. Depletion of the long ncRNA expressed from the RB1 promoter, ncRNA-RB1, reveals regulatory effects different from the RB1-controlled transcriptional program. ncRNA-RB1 positively regulates the expression of calreticulin (CALR) that in response to certain therapeutic interventions can translocate from the endoplasmic reticulum to the cell surface, hence activating anticancer immune responses. Knockdown of ncRNA-RB1 in tumor cells reduced expression of CALR, impaired the translocation of the protein to the cell surface upon treatment with anthracylines and consequently inhibited the cellular uptake by macrophages. In conclusion, co-transcription of ncRNA-RB1 and RB1 provides a positive link between the expression of the two tumor suppressors RB1 and the immune-relevant CALR protein. This regulatory interplay exemplifies disease-relevant co-regulation of two distinct gene products, in which loss of expression of one oncosuppressor protein entails the abolition of additional tumor-inhibitory mechanisms.

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Acknowledgements

Work in the laboratories of GK and OK are suppported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; AXA Chair for Longevity Research; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). Work in the laboratory of UAØ is supported by the German Ministry of education and research through the Alexander von Humboldt Foundation Sofja Kovalevskaja Award.

Author Contributions

A-SM conceived the experiments, performed all experiments except those in Figure 6 and interpreted the data. XH and SR performed the experiments in Figure 6. EN and AM performed bioinformatic analysis. GK and OK conceived the experiments in Figure 6, supervised research and interpreted data. UAØ conceived the experiments, supervised research and interpreted data. A-SM, GK, OK and UAØ wrote the manuscript. All authors read and approved the manuscript.

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Authors and Affiliations

  1. Noncoding RNA Research Group, Max Planck Institute for Molecular Genetics, Berlin, Germany

    A-S Musahl, E Ntini & U A Ørom

  2. Team11, Equipe labellisée Ligue contre le Cancer, INSERM U1138, Cordeliers Research Cancer, Paris, France

    X Huang, G Kroemer & O Kepp

  3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    X Huang, G Kroemer & O Kepp

  4. Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France

    X Huang, G Kroemer & O Kepp

  5. Gustave Roussy, Villejuif, France

    S Rusakiewicz

  6. INSERM, U1015; CICBT507, Villejuif, France

    S Rusakiewicz

  7. Department of Computational Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany

    A Marsico

  8. RNA Bioinformatics group, Max Planck Institute for Molecular Genetics, Berlin, Germany

    A Marsico

  9. Free University of Berlin, Berlin, Germany

    A Marsico

  10. Université Pierre et Marie Curie, Paris, France

    G Kroemer

  11. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    G Kroemer

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  1. A-S Musahl
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Correspondence to U A Ørom.

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Musahl, AS., Huang, X., Rusakiewicz, S. et al. A long non-coding RNA links calreticulin-mediated immunogenic cell removal to RB1 transcription. Oncogene 34, 5046–5054 (2015). https://doi.org/10.1038/onc.2014.424

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