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The c-MYC/NAMPT/SIRT1 feedback loop is activated in early classical and serrated route colorectal cancer and represents a therapeutic target

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Abstract

We have recently identified a positive feedback loop in which c-MYC increases silent information regulator 1 (SIRT1) protein level and activity through transcriptional activation of nicotinamide phosphoribosyltransferase (NAMPT) and NAD+ increase. Here, we determined the relevance of the c-MYC–NAMPT–SIRT1 feedback loop, including the SIRT1 inhibitor deleted in breast cancer 1 (DBC1), for the development of conventional and serrated colorectal adenomas. Immunohistochemical analyses of 104 conventional adenomas with low- and high-grade dysplasia and of 157 serrated lesions revealed that elevated expression of c-MYC, NAMPT, and SIRT1 characterized all conventional and serrated adenomas, whereas DBC1 was not differentially regulated. Analyzing publicly available pharmacogenomic databases from 43 colorectal cancer cell lines demonstrated that responsiveness towards a NAMPT inhibitor was significantly associated with alterations in PTEN and TGFBR2, while features such as BRAF or RNF43 alterations, or microsatellite instability typical for serrated route colorectal cancer, showed increased sensitivities for inhibition of NAMPT and SIRT1. Our findings suggest an activation of the c-MYC–NAMPT–SIRT1 feedback loop that may crucially contribute to initiation and development of both routes to colorectal cancer. Targeting of NAMPT or SIRT1 may represent novel therapeutic strategies with putative higher sensitivity of the serrated route colorectal cancer subtype.

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Acknowledgements

This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) Grant (# Me1719/3-1) (support to AM). We thank A. Heier for her expert support and experimental assistance.

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Authors and Affiliations

  1. Department of Pathology, Ludwig-Maximilians University (LMU), Thalkirchnerstraße 36, 80337, Munich, Germany

    Lydia Brandl, Jens Neumann, Andrea Sendelhofert & Thomas Kirchner

  2. Research group “Signaling pathways in colorectal cancer”, Department of Pathology, Ludwig-Maximilians University (LMU), Thalkirchnerstraße 36, 80337, Munich, Germany

    Nina Kirstein & Antje Menssen

  3. Department of Pathology, Klinikum Bayreuth, Preuschwitzer Str. 101, 95445, Bayreuth, Germany

    Michael Vieth

  4. German Consortium for Translational Cancer Research (DKTK), DKTK site Munich, DKFZ, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Thomas Kirchner

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  1. Lydia Brandl
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Brandl, L., Kirstein, N., Neumann, J. et al. The c-MYC/NAMPT/SIRT1 feedback loop is activated in early classical and serrated route colorectal cancer and represents a therapeutic target. Med Oncol 36, 5 (2019). https://doi.org/10.1007/s12032-018-1225-1

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