One of the most important metabolisms altered in cancer cells is One Carbon Metabolism (OCM), a complex network fuelling the synthesis of nucleotides, NADPH and methylation factors, exploitable by cancer cells to grow and proliferate without control. Serine hydroxymethyltransferase (SHMT) is an enzyme known to play a crucial role in OCM: it catalyses the reversible conversion of serine and tetrahydrofolate into glycine and 5,10 methylenetetrahydrofolate. Moreover, in my group during last years, a new characteristic of this protein came out: it¿ s not only a metabolic enzyme, but it is also a moonlighting protein, in fact it has the ability to bind nucleic acid (DNA and RNA). SHMT1 has the ability to bind and regulate the expression of its mitochondrial isoform by binding to the 5¿ untranslated region of the SHMT2 transcript (UTR), regulating its expression. We also observed that this RNA binding selectively inhibits the SHMT1 enzymatic activity: the conversion of serine to glycine is significantly affected in presence of inhibitory RNA sequences. These results suggest that the RNA-mediated inhibition may contribute to the control of serine consumption by SHMT1. Although several molecules have been proposed and tested in the past years, unfortunately at the moment there aren¿t SHMT inhibitors that can be successfully used in vivo, for this reason our aim is to find a completely new approach. Due to the capability of RNA binding, our goal is to test specific RNA sequences as SHMT inhibitors. The results emerging from this study could be so useful for the development of new nucleic acid- based inhibitors of SHMT, providing a novel chemotherapy strategy.
In our research project there are several innovative aspects that could permit us to have a deeper knowledge regarding the biological function of human serine hydroxymethyltransferase as RNA binding protein. Firstly, we propose to examinate the existence of a SHMT riboregulation: preliminary data in vitro demonstrate that RNA can affect SHMT1 activity (3) and determinate a different concentration of serine and glycine, substrates of reaction catalysed by SHMT. We want to investigate if, also in cells, RNA can act as a key regulator of the amount of serine and glycine. Tuning amino acids concentrations is crucial for cell behaviour and fate: our results could demonstrate that RNA can modulate function of proteins (consequently amino acids concentrations) depending on their cellular localization. Secondly, we want to generate a molecular tool to fine regulate RNA expression inside the cells with the aim to affect SHMT activity: in this way we could have a system to target one of the most important gene involved in OCM, overexpressed in tumours, and so own a key to kill cancer cells. We could find an alternative way to kill cancer cells, not based on the degradation of protein targets or on the choice to target a master gene of tumorigenesis as happens with current RNA-therapies approaches, but on RNA that ribo-regulates the protein which binds it. Moreover, we could hypothesize to exploit the selectivity of RNA as modulator of SHMT to develop a new kind of anti-tumour chemotherapy. Up to date a major part of SHMT inhibitors are proteins, instead we could use RNA as SHMT nucleic acid-base inhibitor, for example creating a specific RNA aptamer. In oncology studies, there is an increasing advancement in the use of aptamers-based therapy (19): indeed, combining the aptamer technology with the evidence of riboregulation of metabolic enzyme involved in cancer, we could hypothesize to generate a RNA aptamer to regulate SHMT and lower its oncogenic potential.
(3) Guiducci, G. et al. (2019) The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism Nucleic Acids Research, 47, 8,4240¿4254.
(19) Fu Z, Xiang J. (2020) Aptamers, the Nucleic Acid Antibodies, in Cancer Therapy. Int J Mol Sci.; 21(8):2793.