Importance of MYC IRES in intestinal homeostasis and carcinogenesis

• Applicant: Professor Dr. Armin Wiegering
• Subject Area: General and Visceral Surgery
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449152914

Colorectal carcinomas (CRC) are the most common tumors of the gastrointestinal tract. At the molecular level, almost all CRCs upregulate the oncogene MYC and are dependent on it. However, due to its function as a transcription factor, MYC is not susceptible to direct inhibition. It is therefore of interest to identify biological processes through which the expression or function of MYC can be indirectly inhibited. It is clearly shown in the literature that protein biosynthesis in tumors is altered in a variety of ways and differs significantly from translation in normal tissue. This includes the use of different translation initiation and elongation factors as well as translation via CAP-independent "Internal Ribosome Entry Sides" (IRES). These differences in translation initiation result in tumor-specific therapeutic approaches. MYC as the driving oncogene in the CRC has an IRES in its 5´UTR that represents such a vulnerable point. While translation via the IRES of MYC is essential in the embryonic organism, no translation via the IRES of MYC takes place in the adult, unstressed organism. In preliminary work we were able to show that in the CRC the MYC protein expression is heavily regulated at the translation level and that this regulation takes place at least partially via the IRES. The central hypothesis of the proposed project is that (i) in CRC the translation of the MYC mRNA takes place via the IRES, (ii) this form of translation is regulated by specific factors and (iii) an inhibition of the IRES-mediated translation reduce the MYC expression in CRCs. On the other hand, we suspect that inhibition of IRES-mediated translation is not essential during normal tissue homeostasis and a reduction in IRES-mediated translation can be tolerated in the whole organism. By this, inhibition of the IRES-mediated translation of MYC represents a specific therapeutic approach for colorectal cancer.The following points are therefore addressed in this application: (i) Proteins are identified which bind to the IRES of the MYC mRNA and it is clarified whether these factors are essential for the increased translation of the MYC mRNA in tumors with the aim of creating new potential therapeutic starting points. (ii) The importance of the IRES of MYC in the context of intestinal proliferation and oncogenesis is characterized with the aim of determining whether inhibition of the IRES-mediated translation of MYC enables tumor-specific therapy. (iii) Cymarin is characterized as a potential inhibitor of IRES-mediated translation of MYC, with the aim of determining whether cymarin shows therapeutic efficacy for CRC at non-toxic doses and to investigate via which target structure in CRC cells this is mediated.

• DFG Programme: Research Grants