Open Access
ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity
(Sringer, 2024-05-31) Zamora Álvarez, Irene; Gutiérrez Núñez, Mirian; Pascual, Alex; Pajares Villandiego, María Josefa; Barajas Vélez, Miguel Ángel; Perez, Lillian M.; You, Sungyong; Knudsen, Beatrice S.; Freeman, Michael R.; Encío Martínez, Ignacio; Rotinen Díaz, Mirja Sofia; Ciencias de la Salud; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB; Gobierno de Navarra / Nafarroako Gobernua
Purpose: tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. Methods: we analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. Results: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. Conclusions: the transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.
Open Access
Transcriptional regulation of type 11 17β-hydroxysteroid dehydrogenase expression in prostate cancer cells
(Elsevier, 2011) Rotinen Díaz, Mirja Sofia; Villar Bécares, Joaquín; Celay Leoz, Ion; Serrano Mendioroz, Irantzu; Notario, Vicente; Encío Martínez, Ignacio; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Type 11 Hydroxysteroid (17-beta) dehydrogenase (HSD17B11) catalyzes the conversion of 5α-androstan-3α,17β-diol into androsterone suggesting that it may play an important role in androgen metabolism. We previously described that overexpression of C/EBPα or C/EBPβ induced HSD17B11 expression in HepG2 cells but this process was not mediated by the CCAAT boxes located within its proximal promoter region. Here, we study HSD17B11 transcriptional regulation in prostate cancer (PC) cells. Transfection experiments showed that the region −107/+18 is sufficient for promoter activity in PC cells. Mutagenesis analysis indicated that Sp1 and C/EBP binding sites found in this region are essential for promoter activity. Additional experiments demonstrated that ectopic expression of Sp1 and C/EBPα upregulated HSD17B11 expression only in PC cell lines. Through DAPA and ChIP assays, specific recruitment of Sp1 and C/EBPα to the HSD17B11 promoter was detected. These results show that HSD17B11 transcription in PC cells is regulated by Sp1 and C/EBPα.
Open Access
Scaffold attachment factor B1 regulates androgen degradation pathways in prostate cancer
(E-Century Publishing, 2021) Yang, Julie Suan-Wei; Qian, Chen; You, Sungyong; Rotinen Díaz, Mirja Sofia; Posadas, Edwin M.; Freedland, Stephen J.; Di Vizio, Dolores; Kim, Jayoung; Freeman, Michael R.; Ciencias de la Salud; Osasun Zientziak
The nuclear matrix protein Scaffold Attachment Factor B1 (SAFB1, SAFB) can act in prostate cancer (PCa) as an androgen receptor (AR) co-repressor that functions through epigenetic silencing of AR targets, such as prostate specific antigen (PSA, KLK3). Genomic profiling of SAFB1-silenced PCa cells indicated that SAFB1 may play a role in modulating intracrine androgen levels through the regulation of UDP-glucuronosyltransferase (UGT) genes, which inactivate steroid hormones. Gene silencing of SAFB1 resulted in increased levels of free dihydrotesterosterone (DHT), and increased resistance to the AR inhibitor enzalutamide. SAFB1 silencing suppressed expression of the UDP-glucuronosyltransferase family 2 member B15 gene (UGT2B15) and the closely related UGT2B17 gene, which encode proteins that irreversibly inactivate testosterone (T) and DHT. Analysis of human data indicated that genomic loss at the SAFB locus, or down-regulation of expression of the SAFB gene, is associated with aggressive PCa. These findings identify SAFB1 as an important regulator of androgen catabolism in PCa and suggest that loss or inactivation of this protein may promote AR activity by retention of active androgen in tumor cells.
Open Access
Changes in gene expression profiling of apoptotic genes in neuroblastoma cell lines upon retinoic acid treatment
(Public Library of Science, 2013) Celay Leoz, Ion; Blanco Luquin, Idoia; Lázcoz Ripoll, Paula; Rotinen Díaz, Mirja Sofia; Castresana, Javier S.; Encío Martínez, Ignacio; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
To determine the effect of retinoic acid (RA) in neuroblastoma we treated RA sensitive neuroblastoma cell lines with 9-cis RA or ATRA for 9 days, or for 5 days followed by absence of RA for another 4 days. Both isomers induced apoptosis and reduced cell density as a result of cell differentiation and/or apoptosis. Flow cytometry revealed that 9-cis RA induced apoptosis more effectively than ATRA. The expression profile of apoptosis and survival pathways was cell line specific and depended on the isomer used.
Open Access
ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer
(Oxford University Press, 2024-06-27) Qian, Chen; Yang, Qian; Rotinen Díaz, Mirja Sofia; Huang, Rongrong; Kim, Hyoyoung; Gallent, Brad; Yan, Yiwu; Cadaneanu, Radu M.; Zhang, Baohui; Kaochar, Salma; Freedland, Stephen J.; Posadas, Edwin M.; Ellis, Leigh; Di Vizio, Dolores; Morrissey, Colm; Nelson, Peter S.; Brady, Lauren; Murali, Ramachandran; Campbell, Moray J.; Yang, Wei; Knudsen, Beatrice S.; Mostaghel, Elahe A.; Ye, Huihui; Garraway, Isla P.; You, Sungyong; Freeman, Michael R.; Ciencias de la Salud; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB
Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.
Open Access
Actionable driver events in small cell lung cancer
(MDPI, 2024) Gutiérrez Núñez, Mirian; Zamora Álvarez, Irene; Freeman, Michael R.; Encío Martínez, Ignacio; Rotinen Díaz, Mirja Sofia; Ciencias de la Salud; Osasun Zientziak
Small cell lung cancer (SCLC) stands out as the most aggressive form of lung cancer, characterized by an extremely high proliferation rate and a very poor prognosis, with a 5-year survival rate that falls below 7%. Approximately two-thirds of patients receive their diagnosis when the disease has already reached a metastatic or extensive stage, leaving chemotherapy as the remaining first-line treatment option. Other than the recent advances in immunotherapy, which have shown moderate results, SCLC patients cannot yet benefit from any approved targeted therapy, meaning that this cancer remains treated as a uniform entity, disregarding intra- or inter-tumoral heterogeneity. Continuous efforts and technological improvements have enabled the identification of new potential targets that could be used to implement novel therapeutic strategies. In this review, we provide an overview of the most recent approaches for SCLC treatment, providing an extensive compilation of the targeted therapies that are currently under clinical evaluation and inhibitor molecules with promising results in vitro and in vivo.
Open Access
Cutting down on lung cancer: Ecliptasaponin A is a novel therapeutic agent
(AME, 2020) Rotinen Díaz, Mirja Sofia; Encío Martínez, Ignacio; Ciencias de la Salud; Osasun Zientziak
This article is a comment of 'Han J, Lv W, Sheng H, et al. Ecliptasaponin A induces apoptosis through the activation of ASK1/JNK pathway and autophagy in human lung cancer cells. Ann Transl Med 2019;7:539'.
Open Access
'Defining the independence of the liver circadian clock' & 'BMAL1-driven tissue clocks respond independently to light to maintain homeostasis'
(Frontiers Media, 2020) Rotinen Díaz, Mirja Sofia; Ciencias de la Salud; Osasun Zientziak
These studies demonstrate that peripheral tissues and organs can detect changes in environmental light and are capable of maintaining some basic functions, independently from our brain clock. The liver can autonomously ensure glucose homeostasis even if there is a glitch in the feedback system to the central clock (SCN). This could be of critical importance in environmentally challenging conditions to the organism. Our body needs to find a fine balance between diving into adjust its clocks in response to environmental stimuli and opposing change; otherwise we would live in a constant jet lag state. These studies provide evidence of the existence of at least two pathways regulating peripheral circadian clocks to reach that equilibrium. The first is an 'immediate and autonomous' response that allows organs to adjust to changes in light, without any input from other circadian clocks. The latter works as a 'fail safe copy' of past light regime that guarantees a certain degree of resistance and robustness to environmental changes, which is sustained by signals coming from other organs. Future studies will need to examine how the autonomous circadian clocks become deregulated in pathological contexts (obesity, metabolic disease, diabetes…).
Open Access
Targeting key players of neuroendocrine differentiation in prostate cancer
(MDPI, 2023) Zamora Álvarez, Irene; Freeman, Michael R.; Encío Martínez, Ignacio; Rotinen Díaz, Mirja Sofia; Ciencias de la Salud; Osasun Zientziak
Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PC) that commonly emerges through a transdifferentiation process from prostate adenocarcinoma and evades conventional therapies. Extensive molecular research has revealed factors that drive lineage plasticity, uncovering novel therapeutic targets to be explored. A diverse array of targeting agents is currently under evaluation in pre-clinical and clinical studies with promising results in suppressing or reversing the neuroendocrine phenotype and inhibiting tumor growth and metastasis. This new knowledge has the potential to contribute to the development of novel therapeutic approaches that may enhance the clinical management and prognosis of this lethal disease. In the present review, we discuss molecular players involved in the neuroendocrine phenotype, and we explore therapeutic strategies that are currently under investigation for NEPC.