TY - JOUR
T1 - DUSP22 suppresses prostate cancer proliferation by targeting the EGFR-AR axis
AU - Lin, Hsiu Ping
AU - Ho, Hui Min
AU - Chang, Cheng Wei
AU - Yeh, Shauh Der
AU - Su, Yu Wen
AU - Tan, Tse Hua
AU - Lin, Wen Jye
N1 - Funding Information:
The authors thank members of T.H.T.'s laboratory and the National RNAi Core Facility (Academia Sinica, Taipei, Taiwan) for technical assistance. The authors thank Dr. Loretta Collins (WriteScience, LLC, Hannewa Falls, NY, USA), for scientific editing. The authors thank Drs. C. P. Chuu [National Health Research Institutes (NHRI)] and Hsing‐Jien Kung (University of California‐Davis, Davis, CA, USA) for providing reagents and cell lines. This study was supported by funding from the National Health Research Institutes (06A1‐IMPP05‐015 to W.‐J.L.), and a Taiwan Ministry of Science and Technology (MOST) grant (106‐2314‐B‐400 ‐010 to W.‐J.L.). C.‐W.C. is a recipient of a MOST postdoctoral fellowship (105‐2811‐B‐400‐014). The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2019/12
Y1 - 2019/12
N2 - Dual-specificity phosphatases (DUSPs) regulate the activity of various downstream kinases through serine or threonine or tyrosine dephosphorylation. Loss of function and aberrant expression of DUSPs has been implicated in cancer progression and poor survival, yet the function of DUSP22 in prostate cancer (PCa) cells is not clear. Gene Expression Omnibus and cBioPortal microarray database analyses showed that DUSP22 expression was lower in PCa tissues than normal prostate tissues, and altered DUSP22 expression was associated with shorter progression-free and disease-free survival of patients with PCa. Exogenous DUSP22 expression in LNCaP, PC3, and C4-2B PCa cells inhibited cellular proliferation and colony formation, supporting a growth inhibitory role for DUSP22 in PCa cells. DUSP22 expression significantly attenuated epidermal growth factor (EGF) receptor (EGFR) and its downstream ERK1/2 signaling by dephosphorylation. However, DUSP22 failed to suppress the growth of CWR22Rv1 and DU145 cells with elevated phosphorylated (p-)ERK1/2 levels. A serine-to-alanine mutation at position 58, a potential ERK1/2-targeted phosphorylation site in DUSP22, was sufficient to suppress growth of CWR22Rv1 cells with elevated p-ERK1/2 levels, suggesting a mutually antagonistic relationship between DUSP22 and ERK1/2 dependent on phosphorylation status. We showed that DUSP22 can suppress prostate-specific antigen gene expression through phosphatase-dependent pathways, suggesting that DUSP22 is an important regulator of the androgen receptor (AR) in PCa cells. Mechanistically, DUSP22 can interact with AR as a regulatory partner and interfere with EGF-induced AR phosphorylation at Tyr534, suggesting that DUSP22 serves as a crucial suppressor of both EGFR and AR-dependent signaling in PCa cells via dephosphorylation. Our findings indicate that loss of function of DUSP22 in PCa cells leads to aberrant activation of both EGFR-ERKs and AR signaling and ultimately progression of PCa, supporting the potential for novel therapeutic design of harnessing DUSP22 in the treatment of PCa.—Lin, H.-P., Ho, H.-M., Chang, C.-W., Yeh, S.-D., Su, Y.-W., Tan, T.-H., Lin, W.-J. DUSP22 suppresses prostate cancer proliferation by targeting the EGFR-AR axis. FASEB J. 33, 14653-14667 (2019). www.fasebj.org.
AB - Dual-specificity phosphatases (DUSPs) regulate the activity of various downstream kinases through serine or threonine or tyrosine dephosphorylation. Loss of function and aberrant expression of DUSPs has been implicated in cancer progression and poor survival, yet the function of DUSP22 in prostate cancer (PCa) cells is not clear. Gene Expression Omnibus and cBioPortal microarray database analyses showed that DUSP22 expression was lower in PCa tissues than normal prostate tissues, and altered DUSP22 expression was associated with shorter progression-free and disease-free survival of patients with PCa. Exogenous DUSP22 expression in LNCaP, PC3, and C4-2B PCa cells inhibited cellular proliferation and colony formation, supporting a growth inhibitory role for DUSP22 in PCa cells. DUSP22 expression significantly attenuated epidermal growth factor (EGF) receptor (EGFR) and its downstream ERK1/2 signaling by dephosphorylation. However, DUSP22 failed to suppress the growth of CWR22Rv1 and DU145 cells with elevated phosphorylated (p-)ERK1/2 levels. A serine-to-alanine mutation at position 58, a potential ERK1/2-targeted phosphorylation site in DUSP22, was sufficient to suppress growth of CWR22Rv1 cells with elevated p-ERK1/2 levels, suggesting a mutually antagonistic relationship between DUSP22 and ERK1/2 dependent on phosphorylation status. We showed that DUSP22 can suppress prostate-specific antigen gene expression through phosphatase-dependent pathways, suggesting that DUSP22 is an important regulator of the androgen receptor (AR) in PCa cells. Mechanistically, DUSP22 can interact with AR as a regulatory partner and interfere with EGF-induced AR phosphorylation at Tyr534, suggesting that DUSP22 serves as a crucial suppressor of both EGFR and AR-dependent signaling in PCa cells via dephosphorylation. Our findings indicate that loss of function of DUSP22 in PCa cells leads to aberrant activation of both EGFR-ERKs and AR signaling and ultimately progression of PCa, supporting the potential for novel therapeutic design of harnessing DUSP22 in the treatment of PCa.—Lin, H.-P., Ho, H.-M., Chang, C.-W., Yeh, S.-D., Su, Y.-W., Tan, T.-H., Lin, W.-J. DUSP22 suppresses prostate cancer proliferation by targeting the EGFR-AR axis. FASEB J. 33, 14653-14667 (2019). www.fasebj.org.
KW - dephosphorylation
KW - dual-specificity phosphatases
KW - MAP kinases
KW - phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=85075960799&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075960799&partnerID=8YFLogxK
U2 - 10.1096/fj.201802558RR
DO - 10.1096/fj.201802558RR
M3 - Article
C2 - 31693867
AN - SCOPUS:85075960799
SN - 0892-6638
VL - 33
SP - 14653
EP - 14667
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -
