A hormone-dependent feedback-loop controls androgen receptor levels by limiting MID1, a novel translation enhancer and promoter of oncogenic signaling

Autor: Köhler, Andrea, Demir, Ümmühan, Kickstein, Eva, Krauss, Sybille, Aigner, Johanna, Aranda-Orgillés, Beatriz, Karagiannidis, Antonios I, Achmüller, Clemens, Bu, Huajie, Wunderlich, Andrea, Schweiger, Michal-Ruth, Schaefer, Georg, Schweiger, Susann, Klocker, Helmut, Schneider, Rainer
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Male
Translation
Cancer Research
Neoplasms
Hormone-Dependent
Ubiquitin-Protein Ligases
genetics [Neoplasms
Hormone-Dependent]
genetics [Prostatic Neoplasms
Castration-Resistant]
biosynthesis [Transcription Factors]
Phosphatidylinositol 3-Kinases
Reciprocal regulation
ddc:570
Cell Line
Tumor
pathology [Neoplasms
Hormone-Dependent]
metabolism [Androgens]
biosynthesis [Microtubule Proteins]
Humans
genetics [Microtubule Proteins]
Promoter Regions
Genetic
metabolism [Phosphatidylinositol 3-Kinases]
Feedback
Physiological
Prostate cancer
metabolism [Receptors
Androgen]
MID1
Research
pathology [Prostatic Neoplasms
Castration-Resistant]
biosynthesis [Nuclear Proteins]
Nuclear Proteins
genetics [Nuclear Proteins]
genetics [Transcription Factors]
Gene Expression Regulation
Neoplastic
Androgen receptor
Prostatic Neoplasms
Castration-Resistant
Oncology
Receptors
Androgen
metabolism [Proto-Oncogene Proteins c-akt]
Androgens
Microtubule Proteins
Molecular Medicine
Proto-Oncogene Proteins c-akt
Signal Transduction
Transcription Factors
Mid1 protein
human
Zdroj: Molecular cancer 13(1), 146 (2014). doi:10.1186/1476-4598-13-146
Molecular Cancer
DOI: 10.1186/1476-4598-13-146
Popis: Background High androgen receptor (AR) level in primary tumour predicts increased prostate cancer (PCa)-specific mortality. Furthermore, activations of the AR, PI3K, mTOR, NFκB and Hedgehog (Hh) signaling pathways are involved in the fatal development of castration-resistant prostate cancer during androgen ablation therapy. MID1, a negative regulator of the tumor-suppressor PP2A, is known to promote PI3K, mTOR, NFκB and Hh signaling. Here we investigate the interaction of MID1 and AR. Methods AR and MID1 mRNA and protein levels were measured by qPCR, Western blot and immunohistochemistry. Co-immunoprecipitation followed by PCR and RNA-pull-down followed by Western blot was used to investigate protein-mRNA interaction, chromatin-immunoprecipitation followed by next-generation sequencing for identification of AR chromatin binding sites. AR transcriptional activity and activity of promoter binding sites for AR were analyzed by reporter gene assays. For knockdown or overexpression of proteins of interest prostate cancer cells were transfected with siRNA or expression plasmids, respectively. Results The microtubule-associated MID1 protein complex associates with AR mRNA via purine-rich trinucleotide repeats, expansions of which are known to correlate with ataxia and cancer. The level of MID1 directly correlates with the AR protein level in PCa cells. Overexpression of MID1 results in a several fold increase in AR protein and activity without major changes in mRNA-levels, whereas siRNA-triggered knockdown of MID1 mRNA reduces AR-protein levels significantly. Upregulation of AR protein by MID1 occurs via increased translation as no major changes in AR protein stability could be observed. AR on the other hand, regulates MID1 via several functional AR binding sites in the MID1 gene, and, in the presence of androgens, exerts a negative feedback loop on MID1 transcription. Thus, androgen withdrawal increases MID1 and concomitantly AR-protein levels. In line with this, MID1 is significantly over-expressed in PCa in a stage-dependent manner. Conclusion Promotion of AR, in addition to enhancement of the Akt-, NFκB-, and Hh-pathways by sustained MID1-upregulation during androgen deprivation therapy provides a powerful proliferative scenario for PCa progression into castration resistance. Thus MID1 represents a novel, multi-faceted player in PCa and a promising target to treat castration resistant prostate cancer.
Databáze: OpenAIRE
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