Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser⁷²⁷ on STAT3 in prostate cancer cells.
Cyclin-dependent kinase 5 (Cdk5) is known to regulate prostate cancer metastasis. Our previous results indicated that Cdk5 activates androgen receptor (AR) and supports prostate cancer growth. We also found that STAT3 is a target of Cdk5 in promoting thyroid cancer cell growth, whereas STAT3 may play a role as a regulator to AR activation under cytokine control. In this study, we investigated the regulation of Cdk5 and its activator p35 on STAT3/AR signaling in prostate cancer cells. Our results show that Cdk5 biochemically interacts with STAT3 and that this interaction depends on Cdk5 activation in prostate cancer cells. The phosphorylation of STAT3 at Ser⁷²⁷ (p-Ser⁷²⁷-STAT3) is regulated by Cdk5 in cells and xenograft tumors. The mutant of STAT3 S727A reduces its interaction with Cdk5. We further show that the nuclear distribution of p-Ser⁷²⁷-STAT3 and the expression of STAT3-regulated genes (junB, c-fos, c-myc, and survivin) are regulated by Cdk5 activation. STAT3 mutant does not further decrease cell proliferation upon Cdk5 inhibition, which implies that the role of STAT3 regulated by Cdk5 correlates to cell proliferation control. Interestingly, Cdk5 may regulate the interaction between STAT3 and AR through phosphorylation of Ser⁷²⁷-STAT3 and therefore upregulate AR protein stability and transactivation. Correspondingly, clinical evidence shows that the level of p-Ser⁷²⁷-STAT3 is significantly correlated with Gleason score and the levels of upstream regulators (Cdk5 and p35) as well as downstream protein (AR). In conclusion, this study demonstrates that Cdk5 regulates STAT3 activation through Ser⁷²⁷ phosphorylation and further promotes AR activation by protein-protein interaction in prostate cancer cells.
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan;
Fu-Ning
FN
Hsu
Mei-Chih
MC
Chen
Kuan-Chia
KC
Lin
Yu-Ting
YT
Peng
Pei-Chi
PC
Li
Eugene
E
Lin
Ming-Ching
MC
Chiang
Jer-Tsong
JT
Hsieh
Ho
H
Lin
D019943:Amino Acid Substitution; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D002467:Cell Nucleus; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011944:Receptors, Androgen / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
C410798:AR protein, human; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012694:Serine; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human
androgen receptor; cyclin-dependent kinase 5; phosphorylation; prostate cancer; signal transducer and activator of transcription 3