POH1/Rpn11/PSMD14: a journey from basic research in fission yeast to a prognostic marker and a druggable target in cancer cells.

Spataro, Vito and Buetti-Dinh, Antoine (2022) POH1/Rpn11/PSMD14: a journey from basic research in fission yeast to a prognostic marker and a druggable target in cancer cells. British Journal of Cancer. (In Press)

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Abstract

POH1/Rpn11/PSMD14 is a highly conserved protein in eukaryotes from unicellular organisms to human and has a crucial role in cellular homeostasis. It is a subunit of the regulatory particle of the proteasome, where it acts as an intrinsic deubiquitinase enzyme removing polyubiquitin chains from substrate proteins. This function is coupled to the translocation of substrates into the core of the proteasome and their subsequent degradation but also, in some instances, to the stabilization of ubiquitinated proteins through their deubiquitinylation. POH1 expression has been observed to be increased in cancer cells of different tissue of origins relative to normal adjacent tissue and to correlate in translational studies with tumour progression, higher tumour grade, decreased sensitivity to cytotoxic drugs and poor prognosis. Proteasome inhibitors targeting the core particle of the proteasome have proved to be highly active drugs in the treatment of multiple myeloma. Inhibitors of POH1 have been developped and some of them (capzimin, thiolutin) have shown promising anticancer activity in cell lines. Here we give an overview of POH1 function in the cell, of its role in oncogenesis, and of early studies with POH1 inhibitors.

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