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Molecular Interplay between AURKA and SPOP Dictates CRPC Pathogenesis via Androgen Receptor

Kumar Nikhil¹, Mohini Kamra¹, Asif Raza¹

¹Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA.

|November 7, 2020

Abstract:

SPOP, an adaptor protein for E3 ubiquitin ligase can function as a tumor-suppressor or a tumor-enhancer. In castration-resistant prostate cancer (CRPC), it inhibits tumorigenesis by degrading many oncogenic targets, including androgen receptor (AR). Expectedly, SPOP is the most commonly mutated gene in CRPC (15%), which closely correlates with poor prognosis. Importantly, 85% of tumors that retain wild-type SPOP show reduced protein levels, indicating that SPOP downregulation is an essential step in CRPC progression. However, the underlying molecular mechanism remains unknown. This study uncovered the first mechanism of SPOP regulation in any type of cancer. We identified SPOP as a direct substrate of Aurora A (AURKA) using an innovative technique. AURKA directly phosphorylates SPOP at three sites, causing its ubiquitylation. SPOP degradation drives highly aggressive oncogenic phenotypes in cells and in vivo including stabilizing AR, ARv7 and c-Myc. Further, SPOP degrades AURKA via a feedback loop. SPOP upregulation is one of the mechanisms by which enzalutamide exerts its efficacy. Consequently, phospho-resistant SPOP fully abrogates tumorigenesis and EMT in vivo, and renders CRPC cells sensitive to enzalutamide. While genomic mutations of SPOP can be treated with gene therapy, identification of AURKA as an upstream regulator of SPOP provides a powerful opportunity for retaining WT-SPOP in a vast majority of CRPC patients using AURKA inhibitors ± enzalutamide, thereby treating the disease and inhibiting its progression.

Insights

SPOP protein downregulation drives castration-resistant prostate cancer progression. Aurora A kinase (AURKA) phosphorylates and degrades SPOP, promoting aggressive tumors. Inhibiting AURKA may restore SPOP function and treat CRPC.

Area of Science:

Oncology
Molecular Biology
Biochemistry

Background:

SPOP protein acts as a tumor suppressor in castration-resistant prostate cancer (CRPC) by degrading oncogenic targets like the androgen receptor (AR).
SPOP is frequently mutated in CRPC, and its downregulation, not just mutation, is linked to poor prognosis, yet the mechanism remained unknown.
Understanding SPOP regulation is crucial for developing targeted CRPC therapies.

Purpose of the Study:

To elucidate the molecular mechanism regulating SPOP protein levels in CRPC.
To identify upstream regulators of SPOP and their role in prostate cancer progression.
To explore therapeutic strategies targeting SPOP regulation in CRPC.

Main Methods:

Utilized innovative techniques to identify SPOP as a direct substrate of Aurora A kinase (AURKA).
Investigated the phosphorylation and ubiquitylation of SPOP by AURKA.
Assessed the in vivo and cellular effects of SPOP degradation on tumorigenesis, epithelial-mesenchymal transition (EMT), and drug sensitivity.

Main Results:

AURKA directly phosphorylates SPOP at three specific sites, leading to its ubiquitylation and degradation.
SPOP degradation stabilizes oncogenic proteins including AR, AR-V7, and c-Myc, driving aggressive phenotypes in vitro and in vivo.
A negative feedback loop was identified where SPOP also degrades AURKA.
Restoring SPOP function via phospho-resistant mutants abrogated tumorigenesis and EMT, sensitizing CRPC cells to enzalutamide.

Conclusions:

AURKA-mediated phosphorylation and degradation of SPOP is a key mechanism driving CRPC progression.
Targeting AURKA with inhibitors offers a therapeutic strategy to restore wild-type SPOP function in CRPC patients, potentially in combination with enzalutamide.
This discovery provides a novel therapeutic avenue for a significant portion of CRPC cases by targeting SPOP regulation.

Read full analysis

Keywords:

Aurora kinase A (AURKA)CRPC SPOP epithelial to mesenchymal transition prostate cancer therapy

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