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  • Review Article
  • Published:

The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target

Nature Reviews Cancer volume 16, pages 463–478 (2016)Cite this article

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Key Points

  • In contrast to all other known prolyl isomerases, PIN1 has the unique property of binding to and catalysing the conversion of specific proline-directed serine/threonine phosphorylation motifs between the two distinct cis and trans conformations of proline. Such PIN1-catalysed prolyl isomerization functions as a molecular timer that modulates many targets at various steps of a given cellular process to synchronously control the amplitude and duration of a given cellular response or process.

  • PIN1 is tightly regulated under physiological conditions, but is commonly overexpressed and/or overactivated in most human cancers, with its levels being correlated with clinical outcome in many cancers. By contrast, PIN1 polymorphisms that lower PIN1 expression are associated with reduced risk for multiple cancers.

  • Pin1-null mice, which develop normally, are highly resistant to tumorigenesis even after overexpression of oncogenes or ablation of tumour suppressors. Conversely, PIN1 overexpression disrupts cell cycle coordination and leads to chromosome instability and tumorigenesis.

  • Abnormal PIN1 activation disrupts the balance in cancer to activate at least 40 oncogenes and inactivate at least 20 tumour suppressors, many of which have a known role in cancer stem cells (CSCs).

  • PIN1 inhibitors have the promising and desirable property of restoring the balance in cancer by simultaneously blocking many cancer-driving pathways in cancer cells and CSCs for treating aggressive and drug-resistant cancers. PIN1 is a major target of the drug all-trans retinoic acid (ATRA) in acute promyelocytic leukaemia.

  • The recent development of cis and trans conformation-specific antibodies provides direct evidence for conformation-specific function and regulation by PIN1, and should facilitate the discovery of novel disease mechanisms and potential new therapies for PIN1-related diseases. Further development of conformation-specific antibodies against oncogenes and tumour suppressors that are PIN1 substrates would provide powerful tools for studying cancer signalling and may lead to new cancer diagnostics and/or therapeutics.

Abstract

Targeted drugs have changed cancer treatment but are often ineffective in the long term against solid tumours, largely because of the activation of heterogeneous oncogenic pathways. A central common signalling mechanism in many of these pathways is proline-directed phosphorylation, which is regulated by many kinases and phosphatases. The structure and function of these phosphorylated proteins are further controlled by a single proline isomerase: PIN1. PIN1 is overactivated in cancers and it promotes cancer and cancer stem cells by disrupting the balance of oncogenes and tumour suppressors. This Review discusses the roles of PIN1 in cancer and the potential of PIN1 inhibitors to restore this balance.

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Figure 1: Abnormal PIN1 activation disrupts the balance between oncogenic and tumour suppressing molecules towards oncogenesis, which might be restored by PIN1 inhibitors.
Figure 2: PIN1 promotes cancer cells and CSCs by activating numerous oncogenes and growth enhancers, and inactivating numerous tumour suppressors and growth inhibitors.
Figure 3: PIN1 promotes the HER2–RAF1–RAS–ERK growth signalling pathway by acting on many substrates at various levels via positive and negative feedback mechanisms.
Figure 4: PIN1 as a major drug target for ATRA in APL therapy.

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Acknowledgements

The authors are grateful to T. Hunter, L. Cantley and P. P. Pandolfi for their expert advice and collaboration, J. Driver for constructive comments on the manuscript, S. Wei for the contribution to Box 1, and to members of the authors' research groups for stimulating discussions. Work conducted in the authors' laboratories is supported by National Institutes of Health (NIH) grants R01CA167677, R03DA031663, R01HL111430, R01AG029385 and R01AG046319, by the Alzheimer's Association grant DVT-14-322623, and the NSFC grant U1205024 to K.P.L. Work is also supported by a Beth Israel Deaconess Medical Center pilot grant and generous gift donations from the Owens Family Foundation to X.Z.Z. and K.P.L.

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  1. Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Xiao Zhen Zhou & Kun Ping Lu

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  1. Xiao Zhen Zhou
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Correspondence to Xiao Zhen Zhou or Kun Ping Lu.

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Competing interests

X.Z.Z. and K.P.L. are inventors of PIN1 technology, which was licensed by Beth Israel Deaconess Medical Center (BIDMC) to Pinteon Therapeutics. Both authors own equity in, and consult for, Pinteon. Their interests were reviewed and are managed by BIDMC in accordance with its conflict of interest policy.

Supplementary information

Supplementary information S1 (table)

Pin1 substrates, targeting sites and functional consequences (PDF 586 kb)

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Glossary

WW domain

A protein-interacting module that contains ∼38 amino acid residues folded into a three-stranded β-sheet structure; the name is derived from two conserved tryptophan residues spaced 20–22 residues apart within the consensus sequence.

ΔNp63α

An alternatively spliced variant of the TP63 gene, a member of the TP53 gene family, encoding a 'short' isoform, which lacks an amino-terminal transactivation domain, exerts oncogenic properties in contrast to the 'long' isoform, p63α, which contains an N-terminal transactivation domain and exerts tumour suppressing properties.

Oncogene switching

After prolonged exposure to a molecularly targeted anticancer drug, cancer cells activate other oncogenic pathways as a mechanism to develop drug resistance.

Parvulin- and PIN1-type PPIases

Although parvulin- and PIN1-type peptidyl-prolyl isomerases (PPIases) belong to a structurally related family, they are further divided into two distinct subfamilies based on their substrate specificity: parvulin-type PPIases cannot isomerize Ser/Thr-Pro motifs after Pro-directed phosphorylation, whereas PIN1-type PPIases isomerize the motifs only after Pro-directed phosphorylation.

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Zhou, X., Lu, K. The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target. Nat Rev Cancer 16, 463–478 (2016). https://doi.org/10.1038/nrc.2016.49

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