Serine synthesis through serine hydroxy-methyl transferases2 (SHMT2) controls keratinocyte proliferation in normal and in pathological conditions

Metabolism supports anabolic reactions and provides the energy needed for cells proliferation. Metabolic reprogramming is therefore needed in different cellular processes, including stem cells self-renewal, proliferation, senescence and differentiation. Here, we focused our attention on the role of serine metabolism, in particular on the Serine Hydroxy-Methyl Transferase 1 and 2 (SHMT1 and SHMT2) enzymes, in maintaining keratinocyte proliferation and its contribution to psoriasis, an hyper-proliferative skin disorder. SHMT1 and SHMT2 are two pyridoxalphosphate (PLP) dependent enzymes involved in the reversible conversion of serine and tetrahydrofolate (THF) to glycine and 5,10-methylene-THF. This reaction represents the major source of methyl group utilized for the de novo nucleotide biosynthesis, DNA methylation, methionine and thymidylate synthesis. SHMT1 and SHMT2 expression levels decrease during calcium-induced keratinocyte differentiation in vitro. Particularly, SHMT2 is important for supporting keratinocyte proliferation and its gene silencing reduces their proliferative capacity. Keratinocytes silenced for SHMT2 reduce their oxygen consumption rate and they are not able to compensate with glycolysis because of extracellular acidification rate (ECAR) reduction. Same results are observed when keratinocytes are treated with SHMTs inhibitor, SHIN1 (SHmts INhibitor 1). Metabolomic analysis shows that keratinocytes silenced for SHMT2 enzyme and treated with SHIN1, are not able to produce nucleotides and methionine and show a reduction of S-adenosilmethionine, the main compound mediating the transfer of methyl groups onto DNA, possibly affecting also epigenetic modifications. Bioinformatic and experimental data show that SHMT2 is implicated in psoriasis. Coherently, a mouse model of psoriasis treated with SHIN1, showed an improvement of some psoriatic hallmarks, including reduction of skin thickness and inflammatory infiltrate. These data suggest that the serine metabolism is important to support keratinocytes expansion and proliferation and its modulation is relevant for the treatment of epidermal hyper-proliferative disorders, holding the promise for therapeutic avenues targeting this specific metabolic pathway.