Interleukin‐6 induces neuroendocrine differentiation (NED) through suppression of RE‐1 silencing transcription factor (REST)

Zhu, Yezi; Liu, Chengfei; Cui, Yuanyuan; Nadiminty, Nagalakshmi; Lou, Wei; Gao, Allen C.

doi:10.1002/pros.22819

Cited by 68 publications

(68 citation statements)

References 27 publications

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“…However, while the loss of REST has been associated with the loss of AR activity, hypoxia, and IL6 expression (33–35), this was not always evident in our sample-set given the continued expression of REST in some NE tumors (36). SRRM4 promotes alternative splicing and inclusion of neural-specific exons (11).…”

Section: Discussionmentioning

confidence: 77%

SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer

Zhang

Coleman

Brown

et al. 2015

Clinical Cancer Research

148

159

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Purpose The neuroendocrine (NE) phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the NE phenotype in CRPC. Experimental Design Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by immunohistochemistry (IHC) in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole genome microarrays. REST splicing was verified by PCR. Results Co-expression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR+/PSA+ (6 patients), 11/22 were AR−/PSA− (4 patients), and 4/24 LuCaP PDXs were AR−/PSA−. By IHC, of the 71 metastases analyzed by whole genome microarrays, 5 metastases were CHGA+/SYP+/AR− and 5 were CHGA+/SYP+/AR+. Only CHGA+/SYP+ metastases had a NE transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the NE signature in CHGA+/SYP+ metastases and all CHGA+/SYP+ LuCaP xenografts. Additionally, expression of SRRM4 in LuCaP NE xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. Conclusions (a) metastatic NE status can be heterogeneous in the same patient, (b) the CRPC NE molecular phenotype can be defined by CHGA+/SYP+ dual positivity, (c) the NE phenotype is not necessarily associated with the loss of AR activity, and (d) the splicing of REST by SRRM4 could promote the NE phenotype in CRPC.

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Section: Discussionmentioning

confidence: 77%

SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer

Zhang

Coleman

Brown

et al. 2015

Clinical Cancer Research

148

159

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“…This finding was confirmed in a subsequent study by showing that the overexpression of exogenous REST abrogates IL-6-induced neuroendocrine differentiation in prostate cancer cells. 27 Taken together we can speculate that truncating mutations in REST may lead to overexpression of TGF-b and IL-6 that increase collagen type 1 synthesis in gingival tissue and results in GF. To show the profibrotic effects of TGFb in gingival fibroblasts, Thompson et al tested the effect of a specific pharmacological inhibitor of TGFb type 1 receptor on the ability of TGFb to induce connective tissue growth factor (which is a marker and mediator of fibrosis, not normally expressed in gingival fibroblasts, but is induced by the potent profibrotic cytokine TGFb and is overexpressed in gingival fibrosis) in gingival fibroblasts.…”

mentioning

confidence: 83%

REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

Bayram

White

Elçioğlu

et al. 2017

The American Journal of Human Genetics

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Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exontruncating mutations in REST for organismal development and the association with the HGF phenotype.

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“…Whole cell extracts were prepared as previously described(29). Protein concentration was determined with Coomassie Plus protein assay kit (Piece, Rockford, IL).…”

Section: Methodsmentioning

confidence: 99%

Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer

Zhu

Liu

Armstrong

et al. 2015

Clinical Cancer Research

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Purpose Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2B-TaxR cells. In this study, we examined if anti-androgens, such as bicalutamide and enzalutamide, could inhibit ABCB1 activity and overcome resistance to docetaxel. Experimental Design ABCB1 efflux activity was determined using a rhodamine efflux assay. ABCB1 ATPase activity was determined by Pgp-Glo™ assay systems. The effects of the anti-androgens bicalutamide and enzalutamide on docetaxel sensitivity were determined by cell growth assays and tumor growth in vivo. Results We found that bicalutamide and enzalutamide inhibit ABCB1 ATP-binding cassette transporter activity through blocking ABCB1 efflux activity. Bicalutamide inhibited ABCB1 efflux activity by 40%, while enzalutamide inhibited ABCB1 efflux activity by ~60%. Both bicalutamide and enzalutamide inhibit ABCB1 ATPase activity. In addition, bicalutamide and enzalutamide inhibit ABCB1 efflux activity and desensitize docetaxel resistant and androgen receptor (AR)-negative DU145 cells. Combination of bicalutamide with docetaxel had a significant anti-tumor effect in both AR-positive and AR-negative docetaxel resistant xenograft models, suggesting that bicalutamide desensitizes docetaxel resistant cells to docetaxel treatment independent of AR status. Conclusions We identified a novel mechanism of action for anti-androgens such as bicalutamide and enzalutamide as inhibitors of ABCB1 efflux and ATPase activity. Bicalutamide and enzalutamide desensitize docetaxel resistant prostate cancer cells to docetaxel treatment independent of AR status. These studies may lead to the development of combinational therapies with bicalutamide/enzalutamide and docetaxel as an effective regiment to treat advanced castration resistant prostate cancer (CRPC) independent of AR status.

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Interleukin‐6 induces neuroendocrine differentiation (NED) through suppression of RE‐1 silencing transcription factor (REST)

Abstract: These results demonstrate that REST functions as a major switch of IL-6 induced neuroendocrine differentiation in LNCaP cells.

Cited by 68 publications

References 27 publications

SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer

SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer

REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer

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