Serine hydroxymethyltransferase (SHMT) is a metabolic enzyme known to be involved in the serine/glycine one-carbon (SGOC) metabolism, where it fuels de novo biosynthesis of purines, pyrimidines, the methylation of homocysteine to methionine and the production of antioxidant molecules. Given their multiple roles, the SHMT isozymes, e.g. the cytosolic (SHMT1) and the mitochondrial (SHMT2), are essential in cancer metabolic reprogramming of human cells and are both considered attractive chemotherapeutic targets. Our group have recently discovered and characterized a non-canonical function of SHMT1 in lung cancer cells, also referred to as ''moonlighting function''. We recently showed that the enzyme has RNA binding properties, indeed it binds to the 5' untranslated region (5'UTR) of SHMT2 with high affinity, affecting the stability and the translation of such transcript. Strikingly, the formation of the enzyme-RNA complex contributes to the modulation of SHMT1 activity inside the cell. Therefore we have proposed a novel regulatory mechanism in which the interaction between SHMT1 and RNA fine-tunes the expression of the mitochondrial SHMT isoform and, at the same time, it modulates the enzymatic activity of the cytosolic counterpart. Surely, our findings are just the tip of an iceberg that needs to be uncovered. Therefore the aim of the present project is to get a better insight into the overall functional relevance of the newly discovered RNA binding ability of SHMT1, unveiling all the RNAs bound by SHMT1 in lung cancer cells and understanding why such interactions take place. Finding a link between cell metabolism and RNA regulation will allow us to better clarify the complex scenario in which SHMT1 and SHMT2 are involved and, moreover, it will be fundamental to find new strategies to target these isozymes in cancer cells.
With a few exceptions, it's not clear why several metabolic enzymes have RNA binding properties [19]. To have some clues it is important to discover which transcripts are bound by these proteins and why, by unraveling step by step the complex network that interconnects enzymatic activity, gene expression and metabolites.
As mentioned above, our recent findings have partially characterized the moonlighting RNA binding activity of SHMT1 in lung cancer cells. By identifying all the RNAs bound by the cytosolic SHMT, the outcome of the present research project would give crucial insights into the overall functional relevance of the moonlighting RNA binding activity of this isozyme in lung cancer, to date still unexplored. In this way we would be able to discover and characterize new layers of regulation in this type of tumor.
Moreover, widening the knowledge on lung cancer metabolic regulation is fundamental to find possible vulnerabilities exploitable for the development of novel tumor therapies. Just as an example, in this case the inhibition properties of the RNA toward the serine cleavage reaction could be exploited to develop inhibitors selective for the cytosolic SHMT. The output of the iCLIP analysis will indeed reveal the consensus sequences and/or secondary structure motifs recognized with high affinity by the enzyme, such information could set the basis to develop molecules with a similar structure (e.g. RNA aptamers) able to selectively bind and inhibit SHMT1. Our working hypothesis is that, given the high sensitivity of lung cancer cells to SHMT1 activity [11,20], the use of the aptamers would likely induce cell death in these cells. Indeed, the doors of the RNA therapeutics are already opened to target several proteins involved in cancer, in this scenario SHMT1 could be a suitable candidate for this innovative therapy in the near future [21].
[19] Albihlal WS et al. (2018) Unconventional RNA-binding proteins: an uncharted zone in RNA biology. FEBS Lett 592(17):2917-2931.
[20] Marani et al. (2016) A pyrazolopyran derivative preferentially inhibits the activity of human cytosolic serine hydroxymethyltransferase and induces cell death in lung cancer cells. Oncotarget 7, 4570-4583.
[21] Morita et al. (2018) Aptamer therapeutics in cancer: current and future. Cancers (Basel) 10(3):80.