Polyribosome targets mediating mRNA decay for cancer prediction and therapy

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DESCRIPTION (provided by applicant): This R21 project aims to identify and characterize novel targets and biomarkers involved in a previously unrecognized cellular mechanism promoting the rapid decay of oncogenic transcripts. While all proteins in a cell are produced from their respective transcripts (mRNAs), those encoding cancer promoting proteins typically carry unique distinguishing features in their 3' untranslated regions. These distinguishing features of oncogenic mRNAs allow for their stability and overexpression (e.g. during cancer development), or for their decay and destruction (e.g. during normal tissue maturation). Our preliminary research has shown that destruction of the cancer promoting mRNA occurs while it is polyribosome associated and where proteins are subject to post-translational modifications like acetylation. Importantly, compartmentalization of this mRNA destruction machinery to the polyribosome facilitates a search for protein isoforms that regulate this switch, revealing novel cancer therapeutic targets. It is known that epigenetic therapy such as histone deacetylase inhibition rapidly induces accelerated decay of ERBB2 and other oncogenic transcripts, putatively via induction of polysome protein post-translational modifications. The first project aim is to isolate and identify by mass spectrometry (MS) polyribosome protein isoforms from breast cancer cells that have their oncogene transcript destruction switch activated by histone deacetylase inhibition. The second project aim is to validate candidate polyribosome protein targets that are demonstrated to be essential in regulating cancer growth as well as the oncogene transcript destruction mechanism, using the technique of RNA interference (RNAi). This project will generate a list of fully characterized, validated, and prioritized polyribosome protein targets and biomarkers known to regulate cancer growth and oncogene transcript stability. This list will contain the most promising polyribosome isoforms for prediction and targeting of an entirely new class of cancer therapeutics that selectively turn off cancer-promoting proteins by inducing their transcript decay.