Mutated SPOP E3 Ligase Promotes 17?HSD4 Protein Degradation to Drive Androgenesis and Prostate Cancer Progression.
Molecular mechanisms underlying intratumoral androgenesis and aberrant androgen receptor (AR) activation in prostate cancer remain poorly understood. Here we demonstrate that ectopic expression of the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger domain protein (SPOP) stabilizes 17?HSD4. SPOP bound a functional substrate-binding consensus (SBC) motif 315RATST319 in 17?HSD4 ... and promoted nondegradable K27- and K29-linked polyubiquitination of 17?HSD4. The effect of SPOP was antagonized by serum- and glucocorticoid kinase-3 (SGK3)-mediated phosphorylation of serine 318 (S318) in the SBC and S318 phosphorylation-dependent binding of SKP2 E3 ligase and subsequent K48-linked polyubiquitination and proteasomal degradation of 17?HSD4. Prostate cancer-associated SPOP mutations impaired the SPOP-17?HSD4 interaction, caused 17?HSD4 protein destruction in prostate cancer cells in culture and patient specimens, and increased testosterone production and prostate cancer cell growth in vitro and in mouse models. Thus, we have identified SPOP and SKP2 as two essential E3 ubiquitin ligases that exert opposite effects on 17?HSD4 protein degradation and intratumoral androgenesis in prostate cancer cells. We further demonstrate that SPOP mutations or SKP2 overexpression contribute to prostate cancer progression by decreasing 17?HSD4 expression and increasing intratumoral androgen synthesis. SIGNIFICANCE: This study reveals a novel mechanism of aberrant AR activation in SPOP-mutated prostate cancer and uncovers putative biomarkers for effective treatment by AR-targeted therapies.
Mesh Terms:
Androgens, Animals, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, SCID, Mutation, Nuclear Proteins, Peroxisomal Multifunctional Protein-2, Prostatic Neoplasms, Proteolysis, Receptors, Androgen, Repressor Proteins, Tumor Cells, Cultured, Ubiquitination, Xenograft Model Antitumor Assays
Androgens, Animals, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, SCID, Mutation, Nuclear Proteins, Peroxisomal Multifunctional Protein-2, Prostatic Neoplasms, Proteolysis, Receptors, Androgen, Repressor Proteins, Tumor Cells, Cultured, Ubiquitination, Xenograft Model Antitumor Assays
Cancer Res
Date: Dec. 01, 2020
PubMed ID: 33762355
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