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June 4th, 2025
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cancer biology
biorxiv

Loss of UFMylation supports prostate cancer metastasis and rewires cell metabolism towards hexosamine biosynthesis

Bozal Basterra, L.Open in Google Scholar•Salazar Palacio, M. C.Open in Google Scholar•Ferreira Campos, A. M.Open in Google Scholar•Demicco, M.Open in Google Scholar•Schmidt, D. R.Open in Google Scholar•Sobczak, K.Open in Google Scholar•Ereno-Orbea, J.Open in Google Scholar•Altea Manzano, P.Open in Google Scholar•Miranda Villanueva, A.Open in Google Scholar•Martinez La Osa, B.Open in Google Scholaret al.

The acquisition of metastatic features in tumor cells encompasses genetic and non-genetic adaptation, including reprogramming of cellular metabolism. Here we show that loss of UFMylation reroutes glucose metabolism, promotes invasive capacity and supports prostate cancer metastasis. Through transcriptome-based bioinformatics analysis, we identified a reduction in the ubiquitin-like modifier UFM1 and its ligase UFL1 in metastatic prostate cancer. We demonstrate that loss of UFMylation results in enhanced cancer cell dissemination and a switch from cellular proliferation to invasion. Using biotin-based proteomics, we identified phosphofructokinase (PFKAP) as an unprecedented UFMylation substrate. Consistent with UFMylation playing a role in the regulation of phosphofructokinase activity, loss of UFMylation reduced glucose metabolism in favour of hexosamine biosynthesis, which resulted in elevated glycosylation of proteins relevant for cell invasion. These results reveal a role for UFMylation in the regulation of phosphofructokinase and glucose metabolism to support prostate cancer metastasis.

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