The epithelium-specific Ets transcription factor, SPDEF, plays a critical role in metastasis of prostate and breast cancer cells. While enhanced SPDEF expression blocks migration and invasion, knockdown of SPDEF expression enhances migration, invasion, and metastasis of cancer cells.
SPDEF expression and activation is tightly regulated in cancer cells; however, the precise mechanism of SPDEF regulation has not been explored in detail. In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway. As a consequence of CDK11p58 mediated degradation of SPDEF, this loss of SPDEF protein results in increased prostate cancer cell migration and invasion. In contrast, knockdown of CDK11p58 protein expression by interfering RNA or SPDEF overexpression inhibit migration and invasion of cancer cells. We demonstrate that CDK11p58 mediated degradation of SPDEF is attenuated by Growth Arrest and DNA damage-inducible 45 (GADD45) α and , two proteins inducing G2/M cell cycle arrest. We show that GADD45 α and γ, directly interact with CDK11p58 and thereby inhibit CDK11p58 activity, and consequentially SPDEF phosphorylation and degradation, ultimately reducing prostate cancer cell migration and invasion. Our findings provide new mechanistic insights into the complex regulation of SPDEF activity linked to cancer metastasis and characterize a previously unidentified SPDEF/CDK11p58/GADD45α/γ pathway that controls SPDEF protein stability and SPDEF-mediated effects on cancer cell migration and invasion.
Oncotarget. 2016 Feb 12 [Epub ahead of print]
Rodrigo E Tamura, Juliano D Paccez, Kristal C Duncan, Mirian G Morale, Fernando M Simabuco, Simon Dillon, Ricardo G Correa, Xuesong Gu, Towia A Libermann, Luiz F Zerbini
International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Werner and Beit Building South, Cape Town, South Africa. , International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Werner and Beit Building South, Cape Town, South Africa. , International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Werner and Beit Building South, Cape Town, South Africa. , International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Werner and Beit Building South, Cape Town, South Africa. , BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. , BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. , Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. , BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. , BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. , International Centre for Genetic Engineering and Biotechnology (ICGEB), Medical Biochemistry Division, Faculty of Health Sciences, University of Cape Town, Werner and Beit Building South, Cape Town, South Africa.