Biology subjects

Cavailles, V.

Publications and source records attributed to Cavailles, V..

4 recordsLinked to original sources

bioRxiv2026

XPO1 controls VDR localization and activity in triple-negative breast cancer cells

The association of cytoplasmic localization of VDR in TNBC tumors and disease aggressivity prompted investigation of its regulation by XPO1. In TNBC cell lines, the XPO1 inhibitors selinexor and eltanexor increased nuclear VDR localization. Their effects were particularly strong when combined with vitamin D treatment. Similarly, XPO1 knockdown increased nuclear VDR levels, both alone and in combination with vitamin D. These results identify XPO1 as an important regulator of VDR subcellular distribution. XPO1 inhibition also enhanced vitamin D-dependent VDR transcriptional activity. Indeed, selinexor, eltanexor, and XPO1 silencing increased vitamin D-dependent CYP24A1 reporter activity and the expression of genes such as CYP24A1 or CDH1. RNA sequencing showed that XPO1 modulation markedly reshaped the vitamin D transcriptional response. The affected genes were mainly involved in metabolism, cell-cycle regulation, protein localization, and cellular organization. Functional analyses demonstrated that cytoplasmic VDR promoted TNBC cell proliferation. Conversely, nuclear VDR was required for the antiproliferative effects of vitamin D. Accordingly, XPO1 inhibition or depletion potentiated vitamin D-mediated growth suppression. This finding suggested functional cooperation between XPO1-dependent export and VDR activity. Finally, high VDR expression was associated with poor disease-free or overall survival only in tumors with high XPO1 expression. Overall, XPO1 negatively regulates VDR nuclear localization and vitamin D responsiveness in TNBC. Targeting XPO1 may therefore enhance the therapeutic potential of vitamin D-based strategies in TNBC.

cell biology↗

bioRxiv2024

The transcription factor RIP140 regulates interferon γ signaling in breast cancer

RIP140 (receptor interacting protein of 140 kDa) is an important player in breast cancer (BC) by regulating key cellular pathways such as nuclear hormone receptors signaling. In order to identify additional genes specifically regulated by RIP140 in BC, we performed an RNA sequencing after silencing its expression in MCF-7 cells. We identified the interferon {gamma} (IFN{gamma}) signaling as being substantially repressed by RIP140 knock-down. Using the GBP1 (guanylate binding protein 1) gene as a reporter of IFN{gamma} signaling, we demonstrated its robust induction by RIP140 through an ISRE motif, leading to a significant reduction of its induction upon IFN{gamma} treatment. Furthermore, we showed that low levels of RIP140 amplified the IFN{gamma}-dependent inhibition of BC cell proliferation. In line with these data, reanalysis of transcriptomic data obtained in human BC samples, revealed that IFN{gamma} levels were associated with good prognosis only for BC patients exhibiting tumors expressing low levels of RIP140, thus confirming its effect on the anti-tumor activity of IFN{gamma} provided by our experimental data. Altogether, this study identifies RIP140 as a new regulator of IFN{gamma} signaling in breast tumorigenesis.

cancer biology↗

bioRxiv2023

RIP140 regulates HES1 oscillatory expression and mitogenic activity in colon cancer cells

BackgroundThe transcription factor RIP140 (Receptor Interacting Protein of 140 kDa) regulates intestinal homeostasis and tumorigenesis through the Wnt signaling. In this study, we have investigated its effect on the Notch/HES1 signaling pathway. MethodsThe impact on HES1 expression and activity was evaluated in colorectal cancer (CRC) cell lines and in transgenic mice, invalidated or not for the Rip140 gene in the intestinal epithelium. A tumor microarray and transcriptomic data sets were used to investigate RIP140 and HES1 expression in relation with patient survival. Statistical comparisons were performed with Mann-Whitney or Kruskal-Wallis or Chi2 tests. ResultsIn CRC cells, RIP140 positively regulated HES1 gene expression at the transcriptional level via an RBPJ/NICD-mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, analyzed by immunohistochemistry, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. ConclusionsOur data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.

cancer biology↗

bioRxiv2020

aiMeRA: A generic modular response analysis R package and its application to estrogen and retinoic acid receptors crosstalk

Modular response analysis (MRA) is a widely used modeling technique to uncover coupling strengths in molecular networks under a steady-state condition by means of perturbation experiments. We propose an extension of this methodology to search genomic data for new associations with a network modeled by MRA and to improve the predictive accuracy of MRA models. These extensions are illustrated by exploring the cross talk between estrogen and retinoic acid receptors, two nuclear receptors implicated in several hormone-driven cancers such as breast. We also present a novel, rigorous and elegant mathematical derivation of MRA equations, which is the foundation of this work and of an R package that is freely available at https://github.com/bioinfo-ircm/aiMeRA/. This mathematical analysis should facilitate MRA understanding by newcomers. Author summaryEstrogen and retinoic acid receptors play an important role in several hormone-driven cancers and share co-regulators and co-repressors that modulate their transcription factor activity. The literature shows evidence for crosstalk between these two receptors and suggests that spatial competition on the promoters could be a mechanism. We used MRA to explore the possibility that key co-repressors, i.e., NRIP1 (RIP140) and LCoR could also mediate crosstalk by exploiting new quantitative (qPCR) and RNA sequencing data. The transcription factor role of the receptors and the availability of genome-wide data enabled us to explore extensions of the MRA methodology to explore genome-wide data sets a posteriori, searching for genes associated with a molecular network that was sampled by perturbation experiments. Despite nearly two decades of use, we felt that MRA lacked a systematic mathematical derivation. We present here an elegant and rather simple analysis that should greatly facilitate newcomers understanding of MRA details. Moreover, an easy-to-use R package is released that should make MRA accessible to biology labs without mathematical expertise. Quantitative data are embedded in the R package and RNA sequencing data are available from GEO.

systems biology↗