UXT Is a LOX-PP Interacting Protein That Modulates Estrogen Receptor Alpha Activity in Breast Cancer Cells

Sánchez-Morgan, Nuria; Kirsch, Kathrin H.; Trackman, Philip C.; Sonenshein, Gail E.

doi:10.1002/jcb.25893

Cited by 21 publications

(19 citation statements)

References 44 publications

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“…Interestingly, interaction between EVI1 and NF-κB has been reported to be important in genomic stability in leukemia [8]. Recent functional studies characterized UXT’s interaction with nuclear receptors, such as ER and AR [9, 10]. Our previous work identified UXT as a transcription factor that directly binds to the AR N-terminus and modulates AR transcriptional activity in prostate cancer cells [10, 11].…”

Section: Introductionmentioning

confidence: 99%

Prostate-specific loss of UXT promotes cancer progression

et al. 2019

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Ubiquitously-expressed, prefoldin-like chaperone (UXT) also called Androgen Receptor Trapped clone-27 (ART-27) is widely expressed in human tissues. Our previous studies showed that UXT regulates transcription repression including androgen receptor (AR) signaling in prostate cancer. Here we analyzed a tissue microarray consisting of normal prostate, benign prostatic hyperplasia, high grade prostatic intraepithelial neoplasia (HGPIN) and primary prostate cancer cases for UXT protein expression. We found that HGPIN and malignant tumors have significantly decreased UXT expression compared to the normal prostate. Loss of UXT expression in primary prostate cancer is positively associated with high Gleason grade and poor relapse-free survival. We engineered prostate-specific UxtKO mice that developed a hyperplastic phenotype with apparent prostate secretion fluid blockage as well as PIN by 4-6 months. Doubly mutant UxtKO/PtenKO mice developed a more aggressive PIN phenotype. UXT depletion in prostate cancer cells also increased retroelements expression, including LINE-1 and Alu. Consistent with this finding UxtKO mice have increased LINE-1 protein levels in the prostate compared to control mice. In addition, cancer cells with UXT depletion have increased retrotransposition activity and accumulated DNA damage. Our findings demonstrate that loss of UXT is an early event during prostate cancer progression, which may contribute to genome instability.

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Section: Introductionmentioning

confidence: 99%

Prostate-specific loss of UXT promotes cancer progression

et al. 2019

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“…Indeed, LOX-PP has been found in the nucleus of several cell types 16 , 17 , and colocalizes with the microtubule network in osteoblastic cells 17 . LOX-PP interacts with intracellular or nuclear proteins, namely HSP70 and c-Raf, CIN85, UXT 18 – 20 and with the intracellular phosphatase domains of receptor-type protein tyrosine phosphatase kappa 21 . The major uptake pathway of recombinant LOX-PP is phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-dependent micropinocytosis, while a secondary pathway depends on dynamin and caveolae 22 .…”

Section: Introductionmentioning

confidence: 99%

Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners

Vallet

Miele

Uciechowska-Kaczmarzyk

et al. 2018

Sci Rep

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Lysyl oxidase (LOX) catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagens and elastin, which is the first step of the cross-linking of these extracellular matrix proteins. It is secreted as a proenzyme activated by bone morphogenetic protein-1, which releases the LOX catalytic domain and its bioactive N-terminal propeptide. We characterized the recombinant human propeptide by circular dichroism, dynamic light scattering, and small-angle X-ray scattering (SAXS), and showed that it is elongated, monomeric, disordered and flexible (Dmax: 11.7 nm, Rg: 3.7 nm). We generated 3D models of the propeptide by coarse-grained molecular dynamics simulations restrained by SAXS data, which were used for docking experiments. Furthermore, we have identified 17 new binding partners of the propeptide by label-free assays. They include four glycosaminoglycans (hyaluronan, chondroitin, dermatan and heparan sulfate), collagen I, cross-linking and proteolytic enzymes (lysyl oxidase-like 2, transglutaminase-2, matrix metalloproteinase-2), a proteoglycan (fibromodulin), one growth factor (Epidermal Growth Factor, EGF), and one membrane protein (tumor endothelial marker-8). This suggests new roles for the propeptide in EGF signaling pathway.

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“…Herein, we identi ed that UXT is also more abundant in breast cancer tissues or cells than normal tissues or cells through analyzing its expression in specimens from breast cancer patients and breast cancer cells, respectively. The reasons for UXT involving in tumor progress were often attributed to enhancing NF-κB activities through forming an integral component of the NF-κB enhanceosome [20], corrupting centrosome activity by forming a novel component of centrosomal processes associated with γ-tubulin [5],or interacting with estrogen receptor or androgen receptor [21,22], and so on. In the present study, we found that UXT negatively regulates the MEG3/p53 axis in a DNMT3bdependent manner to promote the apoptosis and inhibit migration and invasion of breast cancer cells, as well as the growth of nude mice xenograft.…”

Section: Discussionmentioning

confidence: 99%

UXT, a novel DNMT3b-binding protein, promotes breast cancer progression via negatively modulating lncRNA MEG3/p53 axis

Huang

Tang

Shen

et al. 2020

Preprint

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Background UXT is highly expressed in tumor tissues, which function as a vital role in tumor progression. However, the exact role and potential mechanism of UXT in the tumorigenesis of breast cancer remains largely unknown. Methods Expression patterns of UXT and MEG3 were examined using qRT-PCR and western blot, respectively. The capacity of cell proliferation, apoptosis, migration and invasion was assessed using CCK-8, flow cytometry and transwell assays. The methylation of MEG3 promoter was determined using methylation specific PCR. Co-immunoprecipitation was performed to measure the UXT/DNMT3b interaction. RNA-immunoprecipitation was subjected to evaluate the regulation of MEG3 on p53 activity. The xenograft tumor experiment was further conducted to certify the molecular mechanism. Results UXT was up-regulated while MEG3 was down-regulated in breast cancer tissues and cell lines. UXT knockdown or MEG3 overexpression significantly inhibited the proliferation, promoted the apoptosis, and weakened the migration and invasion of MCF7 and ZR75 cells. The hypermethylation of MEG3 promoter was found in breast cancer cells, which was modulated by highly expressed DNMT3b. UXT inhibited the level of MEG3 via recruiting DNMT3b to its promoter. Mechanistically, MEG3 positively regulated the transcriptional activity of p53 via binding with it, thus regulating cell apoptosis, migration and invasion. The xenograft tumor experiment indicated that UXT negatively regulated the MEG3/p53 axis in a DNMT3b-dependent manner to promote the tumor growth. Conclusions UXT, a novel DNMT3b-binding protein, aggravates the progression of breast cancer through MEG3/p53 axis, which may provide a new insight involving in the treatment of breast cancer.

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UXT Is a LOX-PP Interacting Protein That Modulates Estrogen Receptor Alpha Activity in Breast Cancer Cells

Cited by 21 publications

References 44 publications

Prostate-specific loss of UXT promotes cancer progression

Prostate-specific loss of UXT promotes cancer progression

Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners

UXT, a novel DNMT3b-binding protein, promotes breast cancer progression via negatively modulating lncRNA MEG3/p53 axis

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