SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression.
The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.
Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Wenjian
W
Gan
Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Xiangpeng
X
Dai
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Andrea
A
Lunardi
Department of Pathology and Urology, Jonson Comprehensive Cancer Center and Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Zhen
Z
Li
Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Hiroyuki
H
Inuzuka
Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Pengda
P
Liu
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Shoreh
S
Varmeh
Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Jinfang
J
Zhang
Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Liang
L
Cheng
Department of Pathology and Urology, Jonson Comprehensive Cancer Center and Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Yin
Y
Sun
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
John M
JM
Asara
Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Andrew H
AH
Beck
Department of Pathology and Urology, Jonson Comprehensive Cancer Center and Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Jiaoti
J
Huang
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: ppandolf@bidmc.harvard.edu.
Pier Paolo
PP
Pandolfi
Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: wwei2@bidmc.harvard.edu.
Wenyi
W
Wei
D000595:Amino Acid Sequence; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D044842:Cullin Proteins / Q000378:metabolism; D018450:Disease Progression; D005047:Etoposide / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D012097:Repressor Proteins / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins / Q000502:physiology; D054875:Ubiquitination
D000972:Antineoplastic Agents, Phytogenic; C503645:CUL3 protein, human; D044842:Cullin Proteins; C072312:ERG protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; C509761:SPOP protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins; D005047:Etoposide