The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation

Abstract

BackgroundDocetaxel based therapy is one of the first line chemotherapeutic agents for the treatment of metastatic castrate-resistant prostate cancer. However, one of the major obstacles in the treatment of these patients is docetaxel-resistance. Defining the mechanisms of resistance so as to inform subsequent treatment options and combinations represents a challenge for clinicians and scientists.Previous work by our group has shown complex changes in pro and anti-apoptotic proteins in the development of resistance to docetaxel. Targeting these changes individually does not significantly impact on the resistant phenotype but understanding the central signalling pathways and transcription factors (TFs) which control these could represent a more appropriate therapeutic targeting approach.MethodsUsing a number of docetaxel-resistant sublines of PC-3 cells, we have undertaken a transcriptomic analysis by expression microarray using the Affymetrix Human Gene 1.0 ST Array and in conjunction with bioinformatic analyses undertook to predict dysregulated TFs in docetaxel resistant prostate cancer. The clinical significance of this prediction was ascertained by performing immunohistochemical (IHC) analysis of an identified TF (SRF) in the metastatic sites from men who died of advanced CRPC. Investigation of the functional role of SRF was examined by manipulating SRF using SiRNA in a docetaxel-resistant PC-3 cell line model.ResultsThe transcription factors identified include serum response factor (SRF), nuclear factor kappa-B (NFκB), heat shock factor protein 1 (HSF1), testicular receptor 2 & 4 (TR2 &4), vitamin-D and retinoid x receptor (VDR-RXR) and oestrogen-receptor 1 (ESR1), which are predicted to be responsible for the differential gene expression observed in docetaxel-resistance. IHC analysis to quantify nuclear expression of the identified TF SRF correlates with both survival from date of bone metastasis (p = 0.003), survival from androgen independence (p = 0.00002), and overall survival from prostate cancer (p = 0.0044). Functional knockdown of SRF by siRNA demonstrated a reversal of apoptotic resistance to docetaxel treatment in the docetaxel-resistant PC-3 cell line model.ConclusionsOur results suggest that SRF could aid in treatment stratification of prostate cancer, and may also represent a therapeutic target in the treatment of men afflicted with advanced prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3100-4) contains supplementary material, which is available to authorized users.

Role of serum response factor expression in prostate cancer biochemical recurrence

“…In line with previous studies, we have also shown a negative association between SRF nuclear positivity in bone metastases of patients who died of prostate cancer and survival from time of diagnosis and time of castration‐resistance . In the same cohort of patients, we also demonstrated that higher expression of SRF correlated with shorter survival in the context of docetaxel resistance . The aim of this study was to assess SRF expression in RP tissues in order to explore SRF association with BCR with the remit of using SRF, alone or in combination with other markers, as a possible biomarker of BCR which can predict the development of distant metastases following RP.…”

“…SRF is a widely expressed TF involved in cellular processes relevant to cancer development and progression including cellular proliferation and cytoskeletal organization as well as cellular growth, differentiation, and resistance to apoptosis . The association of SRF protein expression with prostate cancer and its relevance to patient survival has been shown in several studies . We have demonstrated SRF clinical relevance in CRPC by immunohistochemical staining of transurethral resections of the prostate in patients who failed hormone ablation therapy with the prostate in situ .…”

Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms

“…A Reactome pathway enrichment analysis 39,40 of all 150 TF’s yielded numerous significant associations (FDR-adjusted p -value < 5.00 × 10 –7 ) in several pathway hierarchies relevant to transcription, epigenetics, and oncogenesis (Supplementary Table 12). Furthermore, TFBS inferred from DNAse-seq footprinting in non-prostate cell lines or Position Weight Matrices (PWM) included recurrent motifs for SRF, ZFP105, ELF3, FOXP1, and TCFAP2E, some with known roles in PrCa regulation or prognosis 41–43 .…”

Epilepsy Associates with Decreased HIF-1α/STAT5b Signaling in Glioblastoma

“…SRF depletion has been associated with increased seizure frequency in a mouse model [49,50]. Interestingly, SRF has also been linked to tumor invasion, proliferation, metastasis and resistance to therapy in different cancer types [51,52,53]. Its role in glioblastoma remains to be explored.…”