PDEF downregulates stathmin expression in prostate cancer

Abstract

Abstract. The Ets proteins are a family of transcription factors characterized by an evolutionarily conserved DNA binding domain that controls key cellular processes. Prostate-derived Ets transcription factor (PDEF), a member of the Ets family, is reported to be present in tissues with high epithelial content, notably breast and prostate. However, the role of PDEF in cancer development is not fully understood. To gain insight into the molecular mechanisms associated with prostate cancer progression, we employed iTRAQ labeling followed by mass spectrometric (MS) analysis to identify candidate proteins that are differentially expressed in prostate cancer cells with or without PDEF. To this end, we overexpressed PDEF in PC3 human prostate cells using a tetracycline inducible system (Tet-On). Many differentially expressed proteins which play important roles in various cellular and biological processes were identified. Among them, stathmin (STMN), which is a microtubule (MT)-destabilizing protein, was found to be downregulated in multiple analyses. We demonstrated that re-expression of STMN reversed the antitumor properties of PDEF in PDEF-overexpressing PC3 cells. Using in vitro functional assays, we showed that STMN overexpression counteracted PDEF's effects against cell proliferation, colony formation and tumor migration. Similar results were further confirmed with the prostate cancer cell line CWR22rv1. In conclusion, many differentially expressed proteins were identified and STMN was found to be downregulated by PDEF.These results suggest that PDEF may inhibit prostate cancer progression by transcriptional downregulation of oncogenic STMN expression. Analyzing the association among differentially expressed proteins may provide a basis to better understand the molecular mechanisms underlying the process of cancer progression and development and further aid in designing therapeutics in the future. IntroductionProstate cancer is the most common cancer diagnosed among men and the second leading cause of death in American men, behind only lung cancer. The American Cancer Society (ACS) estimates about 1 man in 36 will die of prostate cancer (1). Although screening for prostate cancer, based on prostate specific antigen (PSA) has revolutionized early detection and diagnosis of the disease, the challenge that clinicians face are to determine which patients progress to aggressive disease (2,3). In order to determine the possibility of disease progression and ability to manage patient outcomes, it is necessary to better understand the molecular processes underlying the disease development and progression. Gene regulation is an important process in maintaining the integrity of cells for their proper growth and survival. Improper regulation of genes can lead to various diseases like cancer. The Ets family of transcription factors has been long investigated for their role in genetic loss of cellular homeostasis which results in development of various cancers. So far, 25 human and 26 murine Ets family members have been report...

The androgen-induced protein AIbZIP facilitates proliferation of prostate cancer cells through downregulation of p21 expression

“…However, several groups reported that SPDEF is a negative regulator of cell proliferation in some cancer types including prostate cancer4041. It was shown that overexpression of SPDEF in PC-3 cells inhibited proliferation and induced apoptosis via negative regulation of stathmin and survivin expression3641. Taken together with our findings, SPDEF has different roles in the regulation of androgen-sensitive and -insensitive prostate cancer cell proliferation.…”

“…Knockdown of AIbZIP , which is a direct target of SPDEF, suppressed the proliferation of prostate cancer cells, indicating that AIbZIP functions downstream of SPDEF as a major regulator of proliferation in these cells. However, several groups reported that SPDEF is a negative regulator of cell proliferation in some cancer types including prostate cancer4041. It was shown that overexpression of SPDEF in PC-3 cells inhibited proliferation and induced apoptosis via negative regulation of stathmin and survivin expression3641.…”

Stathmin-dependent molecular targeting therapy for malignant tumor: the latest 5 years’ discoveries and developments

“…It is reported that prostate-derived Ets transcription factor (PDEF) is present in breast and prostate cells and tissues. It seems that high expression of stathmin brings down the effects that PDEF inhibit cell proliferation, colony formation and tumor migration, and discloses that PDEF exert an antitumor effects through down-regulating the expression of oncogenic stathmin [ 65 ] (Fig. 4 c).…”

Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor‐Initiating Stem‐Like Cells

“…[36] Overexpression of miR-150 in CD133 (+) TICs leads to inhibition of self-renewal and tumor growth via interaction with the 3'UTR of c-Myb mRNA. [37] miR-22 promotes Hepatitis-B virus related HCC development through down-regulation of estrogen receptor alpha (ER𝛼) transcription. [38] More interestingly, expression of these miRNAs often coincides with epigenetic changes to alter target gene expression.…”