p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer.

Abstract

SCFSkp2/Cks1 ubiquitinates Thr187-phosphorylated p27 for degradation. Overexpression of Skp2 coupled with underexpression of p27 are frequent characteristics of cancer cells. When the role of SCFSkp2/Cks1-mediated p27 ubiquitination in cancer was specifically tested by p27 Thr187-to-Ala knockin (p27T187A KI), it was found dispensable for KrasG12D-induced lung tumorigenesis but essential for Rb1-deficient pituitary tumorigenesis. Here we identify pRb and p53 doubly deficient (DKO) prostate tumorigenesis as a context in which p27 ubiquitination by SCFSkp2/Cks1 is required for p27 downregulation. p27 protein accumulated in prostate when p27T187A KI mice underwent DKO prostate tumorigenesis. p27T187A KI or Skp2 knockdown (KD) induced similar degrees of p27 protein accumulation in DKO prostate cells, and Skp2 KD did not further increase p27 protein in DKO prostate cells that contained p27T187A KI (AADKO prostate cells). p27T187A KI activated an E2F1-p73-apoptosis axis in DKO prostate tumorigenesis, slowed disease progression and significantly extended survival. Querying co-occurrence relationships among RB1, TP53, PTEN, NKX3-1 and MYC in TCGA of prostate cancer identified co-inactivation of RB1 and TP53 as the only statistically significant co-occurrences in metastatic castration-resistant prostate cancer (mCRPC). Together, our study identifies Skp2/Cks1 pocket inhibitors as potential therapeutics for mCRPC. Procedures for establishing mCRPC organoid cultures from contemporary patients were recently established. An Skp2/Cks1 pocket inhibitor preferentially collapsed DKO prostate tumor organoids over AADKO organoids, which spontaneously disintegrated over time when DKO prostate tumor organoids grew larger, setting the stage to translate mouse model findings to precision medicine in the clinic on the organoid platform.

• Authors: H Zhao, Z Lu, F Bauzon, H Fu, J Cui, J Locker, L Zhu
• Journal: Oncogene (Oncogene) Vol. 36 Issue 1 Pg. 60-70 (01 05 2017) ISSN: 1476-5594 [Electronic] England
• PMID: 27181203 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CKS1B protein, human
• E2F1 Transcription Factor
• Retinoblastoma Protein
• S-Phase Kinase-Associated Proteins
• Tumor Protein p73
• Tumor Suppressor Protein p53
• Cyclin-Dependent Kinase Inhibitor p27
• CDC2-CDC28 Kinases

Topics

• Animals
• Apoptosis (genetics)
• CDC2-CDC28 Kinases (metabolism)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (genetics, metabolism)
• Disease Progression
• E2F1 Transcription Factor (metabolism)
• Gene Knock-In Techniques
• Humans
• Male
• Mice
• Mice, Knockout
• Mice, Transgenic
• Neoplasm Staging
• Prostate (metabolism)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Retinoblastoma Protein (deficiency)
• S-Phase Kinase-Associated Proteins (metabolism)
• Tumor Protein p73 (genetics, metabolism)
• Tumor Suppressor Protein p53 (deficiency)
• Ubiquitination