Identification and Characterization of a Novel Androgen Receptor Coregulator ARA267-α in Prostate Cancer Cells
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The androgen receptor (AR) is a member of the steroid receptor superfamily that binds to the androgen response element to regulate target gene transcription. AR may need to interact with some selected coregulators for maximal or proper androgen function. Here we report the isolation of a new AR coregulator with a calculated molecular mass of 267 kDa named the androgen receptor-associated protein 267-α (ARA267-α). ARA267-α contains 2427 amino acids, including one Su(var)3-9,Enhancer-of-zeste, and Trithorax (SET) domain, two LXXLL motifs, three nuclear translocation signal (NLS) sequences, and four plant homodomain (PHD) finger domains. Northern blot analyses reveal that ARA267-α is expressed predominantly in the lymph node as 13- and 10-kilobase transcripts. HepG2 is the only cell line tested that does not express ARA267-α. Yeast two-hybrid and glutathione S-transferase pull-down assays show that both the N and C terminus of ARA267-α interact with the AR DNA- and ligand-binding domains. Unlike other coregulators, such as CBP, which enhance the interaction between the N and C terminus of AR, we found that ARA267-α had little influence on the interaction between the N and C terminus of AR. Luciferase and chloramphenicol acetyltransferase assays show that ARA267-α can enhance AR transactivation in a dihydrotestosterone-dependent manner in PC-3 and H1299 cells. ARA267-α can also enhance AR transactivation with other coregulators, such as ARA24 or PCAF, a histone acetylase, in an additive manner. Together, our data demonstrate that ARA267-α is a new AR coregulator containing the SET domain with an exceptionally large molecular mass that can enhance AR transactivation in prostate cancer cells.Keywords:
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The androgen receptor has been purified in the ‘70s and cloned in the ‘80s. It is a member of the steroid receptor superfamily and mediated the most important effects of androgen in androgen dependent or sensitive tissues. Several physiological function of the brain are differentially controlled in the two sexes and androgens play specific role in the processes of sexual differentiation and it is involved in the maintenance of male sex behaviour in adulthood. When mutated, the androgen receptor may impact on many of these androgen-regulated activities because of a loss of androgenic function in target cells. However, in the case of a peculiar type of mutation, the elongation of the polyglutamine tract normally present in its N-terminus, the androgen receptor becomes neurotoxic and induces cells death of a number of motoneurons in the spinal cord, which express very high level of this protein. Here, we will briefly discuss the most important actions of androgen receptor-mediated androgen activity in the brain and the mechanisms by which the mutant androgen receptor may lead to neurodegeneration in Spinal and Bulbar Muscular Atrophy (SBMA).
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Prostate cancer is the most prevalent cancer in men worldwide and is promoted by the sex hormone androgen. Expression of androgen from the testis can be significantly reduced through castration. However, as most prostate cancer patients acquire castration resistance, additional therapeutic solutions are necessary. Although anti-androgens, such as enzalutamide, have been used to treat castration-resistant prostate cancer (CRPC), enzalutamide-resistant CRPC (Enz-resistant CRPC) has emerged. Therefore, development of novel treatments for Enz-resistant CRPC is urgent. In this study, we found a novel anti-androgen called pinostilbene through screening with a GAL4-transactivation assay. We confirmed that pinostilbene directly binds to androgen receptor (AR) and inhibits its activation and translocalization. Pinostilbene treatment also reduced the protein level and downstream gene expression of AR. Furthermore, pinostilbene reduced the protein level of AR variant 7 in the Enz-resistant prostate cancer cell line 22Rv1 and inhibited cell viability and proliferation. Our results suggest that pinostilbene has the potential to treat Enz-resistant CRPC.
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Androgen receptors(AR) were found in many tissues. And androgen receptor exert its biological effect by binding with androgen. Androgen receptors were influenced by a lot of substance. Among them, androgen plays an important role in the field. For example, androgen can alter the amount, the metabolism and the structure of AR. The influence of androgen on the androgen receptors is reviewed.
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Androgen and the androgen receptor (AR) are critical effectors of prostate cancer. Consequently, androgen deprivation therapy is typically employed as a first-line treatment for prostate cancer patients. While initial responses are generally positive, prostate tumors frequently recur and progress to a lethal form known as castration-resistant prostate cancer (CRPC). Recently, considerable effort has been directed toward elucidating the molecular mechanisms of CRPC. Results from both preclinical and clinical studies suggest that AR-mediated signaling persists and remains functionally important in CRPC despite the elimination of androgens. Understanding the role of this pathway in the development of resistance will therefore be critical to identify alternative diagnostic markers as well as more effective therapies for the treatment of CRPC. Using next-generation sequencing and other high-throughput approaches, numerous groups are beginning to identify the key differences in the transcriptional regulatory and gene expression programs between androgen-dependent and CRPC. A number of mechanisms have been proposed for the differences and these mostly involve alterations to components of the AR co-regulatory network. In this review, we summarize current knowledge on co-regulators of the AR and discuss their potential roles in CRPC. It is anticipated that a deeper understanding of these factors will undercover new targets that can assist in the diagnosis and treatment of CRPC.
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Prostate cancer (PCa) is the second most commonly occurring malignant tumor in Europe and America. Normal and neoplastic growth of prostate gland are dependent on androgen receptor (AR) expression and function. PCa is driven by androgen and its receptor, and they continue to be the key drivers of castration-resistant prostate cancer (CRPC). CRPC is the terminal stage of PCa and seriously jeopardizes the patient's quality of life and lifespan. miRNAs are small noncoding RNAs, 18-25 nt in length that destabilize mRNA or repress protein synthesis by interacting with the 3'-untranslated regions (3'-UTR) of target mRNAs. miRNAs can regulate AR or be regulated by AR and then affect various signaling pathways related to cellular functions and tumor processes. In this review, we focus on the relationship between miRNAs and AR in PCa and elucidate their roles in the induction of malignant changes in PCa.
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Androgen receptor (AR) and its variants play vital roles in development and progression of prostate cancer. To clarify the mechanisms involved in the enhancement of their actions would be crucial for understanding the process in prostate cancer and castration-resistant prostate cancer transformation. Here, we provided the evidence to show that pre-mRNA processing factor 6 (PRPF6) acts as a key regulator for action of both AR full length (AR-FL) and AR variant 7 (AR-V7), thereby participating in the enhancement of AR-FL and AR-V7-induced transactivation in prostate cancer. In addition, PRPF6 is recruited to
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Androgen receptor plays a pivotal role in prostate cancer progression, and androgen deprivation therapy to intercept androgen receptor signal pathway is an indispensable treatment for most advanced prostate cancer patients to delay cancer progression. However, the emerging of castration-resistant prostate cancer reminds us the alteration of androgen receptor, which includes androgen receptor mutation, the formation of androgen receptor variants, and androgen receptor distribution in cancer cells. In this review, we introduce the process of androgen receptor and also its variants’ formation, translocation, and function alteration by protein modification or interaction with other pathways. We dissect the roles of androgen receptor in prostate cancer from molecular perspective to provide clues for battling prostate cancer, especially castration-resistant prostate cancer.
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Recent research provides a more detailed understanding of the androgen and androgen receptor system role in mammalian female physiology indicating the essential value in reproduction. Here, we summarize androgen and androgen receptor biochemical and immunohistochemical brain studies of different vertebrate classes and, in detail, our investigations conducted on the female of the seasonal breeders, the amphibian anura Rana esculenta and the reptile, Podarcis sicula. The results have been achieved seasonally through plasma steroid radioimmunoassay and brain androgen binding activity by biochemical identification as well by androgen receptor immunolocalization and neuroanatomical distribution. Taken together, the seasonal fluctuations and the signal intensity in the different target cells of established encephalic district extend knowledge of the central action of the androgen in the lower vertebrate providing considerable understanding of the physiology role of the androgen/androgen receptor system in the female lower vertebrate reproduction.
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Although androgens have myriad effects on the skeleton, the regulation of androgen action in bone is not well understood. Androgen receptors (ARs) are known to play an important role in mediating androgen action. We have examined the effects of androgens and other sex steroids on AR levels in osteoblastic cells in vitro using two clonal human cell lines, SaOS-2 and U-2 OS. AR protein levels were quantitated both by specific androgen binding studies and Western analyses, and AR messenger RNA was measured with RNase protection assays. Potential changes in AR functionality was assessed by reporter assays. Treatment of osteoblastic cells with the nonaromatizable androgen 5alpha-dihydrotestosterone (DHT) increased specific androgen binding 2-to 4-fold. Similar increases in AR protein levels were documented by Western analysis in both cell lines. The androgen-mediated increase in receptor levels was time and dose dependent as well as androgen specific. Steady-state AR messenger RNA levels were also increased by DHT. When AR concentrations in osteoblastic cells were elevated with exogenous receptor, there was an enhancement of DHT responsiveness, measured by increased trans-activation of an androgen-responsive promoter. Thus, androgen exposure increased androgen receptor protein levels and specific androgen binding in osteoblastic cells. Androgen action as measured by androgen-mediated transcriptional activation is enhanced in the presence of elevated AR levels. Consequently, these studies have revealed an additional means by which androgens may modulate skeletal metabolism.
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