ERRα induces H3K9 demethylation by LSD1 to promote cell invasion

Carnesecchi, Julie; Forcet, Christelle; Zhang, Ling; Tribollet, Violaine; Barenton, Bruno; Boudra, Rafik; Cerutti, Catherine; Billas, I. M. L.; Sérandour, Aurélien A.; Carroll, Jason S.; Beaudoin, Claude; Vanacker, Jean‐Marc

doi:10.1073/pnas.1614664114

Cited by 78 publications

(74 citation statements)

References 62 publications

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“…ERRα binding to a proximal (prox), but not to distal (dist) element of its own human promoter was used as positive and negative controls, respectively ( Fig. 4J) [32,33]. In the absence of added RankL, migration of 4T1-ERRα cells was lower than that of 4T1-CT cells (P = 0.0019), but the opposite was observed after Rankl treatment (P = 0.002: 4T1-CT +Rankl versus 4T1-ERRα+Rankl).…”

Section: Errα Regulates Rank Expression In Bca Cellsmentioning

confidence: 99%

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ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

et al. 2018

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Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-offunction analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1 mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases.

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Section: Errα Regulates Rank Expression In Bca Cellsmentioning

confidence: 99%

“…Quantification of ChIP enrichment was calculated relative to input values. Distal and proximal elements of ERRα gene were used as negative and positive controls, respectively ( Supplementary Table S7) [32,33].…”

Section: Chromatine Immunoprecipitation (Chip)mentioning

confidence: 99%

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

et al. 2018

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“…Most of the efforts to understand the function and specificity of TFs was so far focused on their interaction with regulatory proteins at cis-regulatory modules, so-called enhancers and promoters [5][6][7][8] . However, TFs do not only interact with other TFs but with a variety of proteins including chromatin associated proteins, histone modifiers, factors of the general transcriptional machinery or mRNA regulatory proteins [9][10][11][12][13] . Hence, it is thought that TFs promote cell type diversity by assembling protein interaction networks consisting of different types of proteins in a cell-type-specific manner 6,14,15 .…”

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confidence: 99%

Multi-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity

et al. 2020

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Transcription factors (TFs) control cell fates by precisely orchestrating gene expression. However, how individual TFs promote transcriptional diversity remains unclear. Here, we use the Hox TF Ultrabithorax (Ubx) as a model to explore how a single TF specifies multiple cell types. Using proximity-dependent Biotin IDentification in Drosophila, we identify Ubx interactomes in three embryonic tissues. We find that Ubx interacts with largely non-overlapping sets of proteins with few having tissue-specific RNA expression. Instead most interactors are active in many cell types, controlling gene expression from chromatin regulation to the initiation of translation. Genetic interaction assays in vivo confirm that they act strictly lineage-and process-specific. Thus, functional specificity of Ubx seems to play out at several regulatory levels and to result from the controlled restriction of the interaction potential by the cellular environment. Thereby, it challenges long-standing assumptions such as differential RNA expression as determinant for protein complexes.

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“…Of note is that this phenomenon occurred to a higher extent in the basal-like model than in the luminal A model. Recently, Battaglia et al reported that LSD-1 mediated the epigenetic corruption of vitamin D signaling in prostate cancer [26], and Carnesecchi et al reported a close interaction between ERRα and LSD1 to regulate each other, mostly in cancer cell invasive behavior [27,28]. In particular, LSD-1 was involved in the maintenance of ERRα protein stability, while the ERRα protein induced LSD-1 to erase repressive marks in vitro, thereby promoting the transcriptional activation of genes involved in the invasion of the extracellular matrix.…”

Section: Errα Loss Of Function Abrogated Vdr Genomic Action On Cyp24amentioning

confidence: 99%

“…Astninski et al, indeed, demonstrated that the induction of CYP24A1 by fasting was regulated through a peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-ERRα-dependent mechanism, showing, for the rst time, a role for ERRα in the suppression of vitamin D signaling. Among interactors of VDR, Battaglia et al [26] highlighted the role of Lysine-speci c demethylase 1A (LSD-1), also known as KDM1A, in the corruption of VDR activity in prostate cancer, and Carnesecchi et al [27,28] reported a close interaction between ERRα and LSD-1 to regulate each other, mostly in aggressive cancers. Collectively, these ndings prompted us to evaluate the function of ERRα in the corruption of the VDR signaling network in breast cancer in vitro and through a bioinformatics approach to explore the relevant interactions underlying the biological behavior of ERRα.…”

Section: Introductionmentioning

confidence: 99%

ERRα/VDR Axis Promotes Calcitriol Degradation and Estrogen Signaling Activation and Correlates with Poor Prognosis in Basal-like Breast Cancer Patients.

Danza¹,

Porcelli²,

Summa³

et al. 2020

Preprint

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Background Vitamin D is used to reduce cancer risk and improve the outcome of cancer patients, but the VDR pathway needs to be functionally intact to ensure the biological effects of circulating calcitriol. Besides ERα, another nuclear receptor, ERRα, has recently been shown to interfere with the VDR pathway, but its role in the cytotoxicity and transactivation activity of calcitriol is completely unknown in breast cancer (BC).Methods We investigated the function of ERRα on BC cell proliferation and calcitriol cytotoxicity and transactivation activity by silencing ERRα expression. We then performed a colony formation assay and cell cycle analysis to assess cell proliferation, and western blot and RT-PCR to investigate underlying mechanisms of cytotoxicity and VDR genomic action. Immunofluorescence was used to investigate VDR and ERRα cellular distribution. Bioinformatics analyses were performed to uncover the interaction network of VDR and ERRα. The translational significance of both bioinformatics and in vitro results were studied in the TCGA-BRCA (BReast CAncer) cohort.ResultsERRα functionally supported the proliferation of BC cell lines and acted as a calcitriol-induced co-activator of the VDR complex. As such, ERRα deregulated the calcitriol/VDR genomic action by enhancing CYP24A1 and both ESR1 and aromatase (CYP19A1) expression in calcitriol-treated cells. In contrast, ERRα functionally supported calcitriol cytotoxicity by enhancing calcitriol- induced G0/G1 phase cell cycle arrest and by affecting the expression of cyclin D1 and p21/Waf1. The interactome analysis suggested PPARGC1A and PELP-1 were key players in genomic actions of the calcitriol/VDR/ERRα axis. Evaluation of patients’ outcome in the TCGA dataset definitely showed the translational significance of VDR/ERRα biological effects, highlighting that VDR-CYP24A1-ESRRA overexpression correlates with poor prognosis in basal-like breast cancer setting. ConclusionsCollectively, our findings identified a novel VDR/ERRα axis in breast cancer through which ERRα promotes the corruption of VDR genomic action and drives worsening of prognosis in BC patients.

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ERRα induces H3K9 demethylation by LSD1 to promote cell invasion

Cited by 78 publications

References 62 publications

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

Multi-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity

ERRα/VDR Axis Promotes Calcitriol Degradation and Estrogen Signaling Activation and Correlates with Poor Prognosis in Basal-like Breast Cancer Patients.

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