ERG Oncoprotein Inhibits ANXA2 Expression and Function in Prostate Cancer

Abstract

Overexpression of ERG in the prostate epithelium, due to chromosomal translocations, contributes to prostate tumorigenesis. Here, analysis of ERG siRNA-treated prostate cells harboring the endogenous TMPRSS2-ERG fusion revealed an inverse relationship between ERG and Annexin A2 (ANXA2) expression at both the RNA and protein level. ANXA2, a Ca2+-dependent and phospholipid–binding protein, is involved in various cellular functions, including maintenance of epithelial cell polarity. Mechanistic studies defined the prostate-specific transcription start site of ANXA2 and showed that the recruitment of ERG to the ANXA2 promoter is required for transcriptional repression by ERG. Knockdown of ERG enhanced the apical localization of ANXA2, the bundling of actin filaments at cell-cell junctions and formation of a polarized epithelial phenotype. ERG overexpression disrupted ANXA2 mediated cell polarity and promoted epithelial mesenchymal transition (EMT) by inhibiting CDC42 and RHOA, and by activating cofilin. Immunohistochemistry (IHC), demonstrated a reciprocal relationship of ANXA2 and ERG expression in a large fraction of primary prostate cancer clinical specimens. ANXA2 was absent or markedly reduced in ERG(+) tumors, which were mostly well-differentiated. ERG(−) tumors, meanwhile, expressed moderate to high levels of ANXA2, and were either poorly-differentiated or displayed subsets of poorly-differentiated cells. Taken together, the transcriptional repression of ANXA2 by ERG in prostate epithelial cells plays a critical role in abrogating differentiation, promoting EMT, and in the reciprocal correlation of ERG and ANXA2 expression observed in human prostate cancer. IMPLICATIONS ANXA2 is a new component of the ERG network with potential to enhance biological stratification and therapeutic targeting of ERG stratified prostate cancers.

Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifiesERGas the strongest independent predictor of recurrence

“…A total of 135 probe sets of this CodeSet target transcripts from 121 oncogenes, tumor suppressors, and gene fusion variants associated with prostate cancer and cancer in general. These genes were selected based on their association with cancer, specifically prostate cancer, according to the following criteria, supported by at least two publications: (1) have significant differential gene expression in prostate tumor versus normal comparison based on microarray gene expression profiling (data accessible at NCBI GEO database, accession GSE32448 [24]), including ERG [25, 26], ERG8 [27, 28], ANXA2 [29, 30], MYO6 [31, 32] and MAOA [32, 33]; (2) are regulated by androgen, such as AMACR [25, 34, 35], PSGR [36, 37], PCGEM1 [38, 39], [40, 41], and NKX3.1 [42, 43]; (3) are associated with prognosis of prostate cancer, such as AR [44, 45], EZH2 [46, 47], C-MYC [48, 49], PTEN [50, 51], and NCOA2 [52, 53]; (4) are associated with the ETS family of transcription factors detected in GSE32448 [54, 55]; (5) are commonly rearranged in prostate cancer [26, 56, 57]; (6) are involved in prostate cancer cell invasion, such as SPINK1 [58, 59], TFF3 [60, 61], MMP2 and MMP9 [62, 63]; (7) or are associated with multiple malignancies involving PDGF [64], RAS [65], VEGF [66], EGFR [67], TP53 [65, 68], Interleukin [52], and JAK/STAT signaling pathways [69, 70]. An additional 16 probe sets target five genes that distinguish prostate epithelial from stromal cells [71–74], and 11 house-keeping genes with minimal tumor-normal differential expression identified through gene expression profiling [24] were included as controls.…”

Long non‐coding RNA LUCAT1 promotes tumourigenesis by inhibiting ANXA2 phosphorylation in hepatocellular carcinoma

“…Annexin A2 is proved to be implicated in various cancers, including HCC. 17,[35][36][37][38] For example, Zhang et al reported that shRNA-mediated silencing of ANXA2 suppresses the invasion, migration and tumourigenic potential of hepatoma cells and may thus be utilized as a target of future molecular therapies. 39 As ANXA2 binds with LUCAT1, and considering the desperate need to find a better therapeutic target for HCC patients, we designed subsequent experiments to determine the mechanism of ANXA2 and LUCAT1.…”

Complement activation by autoantigen recognition in the growth process of benign prostatic hyperplasia

“…Therefore, these molecules are expected to function as autoantigens, with their exposure as antigens attributable to various stimuli such as hypoxia, infection, or ischemia. In addition, annexin A2 and Hsp90 have been reported to be associated with the development of prostate cancer by promoting the growth process 26–29 . These reports indicate that annexin and Hsp90 may be associated with the BPH growth process in an as yet unknown manner.…”