Aberrant expression of the neuronal-specific protein DCDC2 promotes malignant phenotypes and is associated with prostate cancer progression.
By integrating gene profiling and immunohistochemical data with functional experiments in cell lines in this study we show for the first time that doublecortin (DCX) domain containing 2 (DCDC2), a protein belonging to the DCX family and involved in neuronal cell migration, is aberrantly expressed in prostate tumors whereas absent in normal prostate. Furthermore, in patients treated with radical prostatectomy, high levels of DCDC2 RNA were significantly associated with increased biochemical relapse (LogRank Mantel-Cox=0.012). Mechanistically, we found that the ETS transcription factor ESE3/EHF, which is expressed in normal prostate and frequently lost in prostate tumors, maintained DCDC2 repressed by binding to a novel identified ETS binding site in the gene promoter. Consistently, in prostate tumors and in cellular models of gain and loss of ESE3/EHF, the expression of DCDC2 and ESE3/EHF were inversely correlated. In prostate cancer cells, DCDC2 colocalized with microtubules and promoted cell migration and resistance to the microtubule-targeting drug taxol. Collectively, this study establishes DCDC2 as a novel ESE3/EHF oncogenic target in prostate cancer. These findings may be relevant for the clinical management of prostate cancer as DCDC2 may signal tumors more prone to relapse and resistant to taxol treatment.
Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
N
N
Longoni
P
P
Kunderfranco
S
S
Pellini
D
D
Albino
M
M
Mello-Grand
S
S
Pinton
G
G
D'Ambrosio
M
M
Sarti
F
F
Sessa
G
G
Chiorino
C V
CV
Catapano
G M
GM
Carbone
D001665:Binding Sites; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D012016:Reference Values; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology
C510451:DCDC2 protein, human; C403306:EHF protein, human; D008869:Microtubule-Associated Proteins; D014157:Transcription Factors; D050257:Tubulin Modulators; D017239:Paclitaxel