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

Abstract

POH1/Rpn11/PSMD14 is a highly conserved protein in eukaryotes from unicellular organisms to human and has a crucial role in cellular homoeostasis. It is a subunit of the regulatory particle of the proteasome, where it acts as an intrinsic deubiquitinase removing polyubiquitin chains from substrate proteins. This function is not only coupled to the translocation of substrates into the core of the proteasome and their subsequent degradation but also, in some instances, to the stabilisation of ubiquitinated proteins through their deubiquitination. POH1 was initially discovered as a functional homologue of the fission yeast gene pad1⁺, which confers drug resistance when overexpressed. In translational studies, expression of POH1 has been found to be increased in several tumour types relative to normal adjacent tissue and to correlate with tumour progression, higher tumour grade, decreased sensitivity to cytotoxic drugs and poor prognosis. Proteasome inhibitors targeting the core particle of the proteasome are highly active in the treatment of myeloma, and recently developed POH1 inhibitors, such as capzimin and thiolutin, have shown promising anticancer activity in cell lines of solid tumours and leukaemia. Here we give an overview of POH1 function in the cell, of its potential role in oncogenesis and of recent progress in developing POH1-targeting drugs.

Fig. 1. Structure of the 26S proteasome and position of POH1 (coloured in red) within the lid of the 19S regulatory particle.

The 3D structure of POH1 within the proteasome is magnified and the position of the JAMM active site is coloured in purple. The figure was prepared with chimera (v1.15) [96] using the crystal structures downloaded from the protein data bank with code 5GJR [97].

Fig. 2. Protein sequence alignment of S. pombe Pad1, human POH1 and other MPN proteins associated with multiprotein complexes CSN5, BRCC36 and eIF3f.

The multiple sequence alignment was made with EMBL-EBI’s tools Clustal Omega and MView [98].

Fig. 3. 3D reconstruction of the interaction between capzimin and POH1 active site.

The figure was prepared with chimera (v1.15) [96] using the crystal structures downloaded from the protein data bank with code 5JOG [99].

Fig. 4. Chemical structures of capzimin, thiolutin and other compounds with predicted POH1-inhibitory activity based on virtual screening.

Structures have been downloaded from the ZINC database [100].