Prolyl Isomerization in Cancer Biology

Prolyl isomerization denotes the reversible conversion between cis and trans conformations of peptidyl‐prolyl bonds in proteins bearing phosphorylated serine or threonine residues adjacent to proline. Catalysed by the unique enzyme Pin1, this conformational switch exerts profound control over protein stability, subcellular localisation and interaction networks. In cancer, dysregulated Pin1 activity amplifies oncogenic signalling by promoting the accumulation and function of drivers such as cyclin‐dependent kinases, transcription factors and survival mediators. Aberrant prolyl isomerization influences cell-cycle progression, DNA damage responses, stem‐cell properties and metabolic reprogramming, thereby contributing to tumour initiation, progression, metastasis and therapeutic resistance. The global impact of this mechanism has prompted intensive investigation into its regulation and its potential as a target for novel anticancer strategies.

Research from Nature Portfolio

Recent studies have revealed that Pin1 stability in glioma stem cells is governed by a deubiquitinase, whose activity is regulated by mitotic kinase phosphorylation. Stabilisation of Pin1 enhances the isomerization of the SUMO-conjugating enzyme Ubc9, leading to hypersumoylation that sustains stem-cell maintenance and tumour growth. Combined inhibition of Pin1 and its upstream kinase yields potent suppression of orthotopic glioma models, highlighting new intervention points to disrupt oncogenic sumoylation circuits.

An earlier seminal work established a covalent inhibitor that selectively binds the catalytic site of Pin1, inducing its degradation and generating reactive oxygen species. This dual-action compound impairs multiple Pin1-dependent pathways, inhibits cancer stem-cell expansion and curbs metastatic growth, providing a proof of principle for targeting prolyl isomerase activity in vivo.

Prolyl Isomerization in Cancer Biology publication trend

The graph below shows the total number of articles in prolyl isomerization in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Peptidyl-prolyl cis-trans isomerase (PPIase): An enzyme that catalyses the interconversion of peptide bonds preceding proline residues.

Pin1: A phospho-specific PPIase that recognises pSer/Thr-Pro motifs and governs conformational dynamics of substrate proteins.

SUMOylation: The covalent attachment of small ubiquitin-like modifier (SUMO) proteins to lysine residues, altering target function.

Deubiquitinase: An enzyme that removes ubiquitin from substrates, thereby rescuing them from proteasomal degradation.

PROTAC: Proteolysis-targeting chimera, a bifunctional molecule that recruits an E3 ligase to a target protein, promoting its ubiquitination and degradation.

Allosteric regulation: Modulation of enzyme activity through ligand binding at a site distinct from the active site.

References

1. Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells. Nature Communications (2024).
2. A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action. Nature Communications (2017).
3. PIN1 and CDK1 cooperatively govern pVHL stability and suppressive functions. Cell Death & Differentiation (2023).
4. Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia. Chemical Science (2024).
5. Dissecting the Allosteric Fine-Tuning of Enzyme Catalysis. JACS Au (2024).
6. Prolyl isomerase Pin1: a promoter of cancer and a target for therapy. Cell Death & Disease (2018).