Specific and redundant activities ofETV1andETV4in prostate cancer aggressiveness revealed by co-overexpression cellular contexts

Abstract

Genomic rearrangements involving ETS transcription factors are found in 50–70% of prostate carcinomas. While the large majority of the rearrangements involve ERG, around 10% involve members of the PEA3 subfamily (ETV1, ETV4 and ETV5). Using a panel of prostate cancer cell lines we found co-overexpression of ETV1 and ETV4 in two cell line models of advanced prostate cancer (MDA-PCa-2b and PC3) and questioned whether these PEA3 family members would cooperate in the acquisition of oncogenic properties or show functional redundancy. Using shRNAs we found that ETV1 and ETV4 have partially overlapping functions, with ETV1 being more relevant for cell invasion and ETV4 for anchorage-independent growth. In vitro expression signatures revealed the regulation of both specific and shared candidate targets that may resemble cellular mechanisms in vivo by interaction with the same intermediate partners. By combining the phenotypic impact data and the gene expression profiles of in vitro models with clinico-pathological features and gene expression profiles of ETS-subtyped tumors, we identified a set of eight genes associated with advanced stage and a set of three genes associated with higher Gleason score, supporting an oncogenic role of ETV1 and ETV4 overexpression and revealing gene sets that may be useful as prognostic markers.

Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer

“…This is in agreement with the observation that rearrangements and expression of ERG, a member of the ETS transcription factor family, are early events in prostate cancer carcinogenesis but most likely lose relevance in more advanced stages (46). Similar to our results, a recent study reported CDK19 as 1 of only 2 candidate genes associated with invasion and aggressiveness from in vivo and in vitro gene expression studies of prostate tumors with rearrangement of another gene from the ETS transcription factor family called ETV-1 (47). In addition, in primary tumors, a correlation of CDK19 levels with Ki-67 protein expression was observed, which has been linked to aggressive prostate cancer and was shown to be an independent prognostic biomarker (48).…”

The ETS Family Transcription Factors Etv5 and PU.1 Function in Parallel To Promote Th9 Cell Development

“…The partial redundancy between PU.1 and Spi-B, two factors in the same sub-family, has been examined in several models including myeloid and lymphoid cell development, B cell function, and the development of leukemia (34–37). Other examples of factors from the same sub-family having overlapping function include ETV1 and ETV4 that cooperate in prostate cancer, ELK1 and ELK4 in thymocyte development, and FLI-1 and ERG in hematopoiesis (38–40). However, PU.1 and ETV5 are from different sub-families.…”

Oncogenic mechanisms of HOXB13 missense mutations in prostate carcinogenesis

“…DU145 cells were acquired from the German Resource Centre for Biological Material (DSMZ, Braunschweig, Germany) and grown at regular growth conditions in RPMI-1640 medium (GIBCO®, Invitrogen, Carlsbad, CA, USA), supplemented with 10% fetal bovine serum (FBS, GIBCO®) and 1% penicillin/streptomycin (GIBCO®). The origin and growth conditions of the remaining cell lines were previously described [43,44]. Conventional G-banding karyotyping was previously performed to confirm cell identity [44].…”

“…The origin and growth conditions of the remaining cell lines were previously described [43,44]. Conventional G-banding karyotyping was previously performed to confirm cell identity [44]. All prostate cell lines were routinely tested for Mycoplasma spp.…”