Metabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets

Alterations in the epigenome and metabolism affect molecular rewiring of cancer cells facilitating cancer development and progression. Modulation of histone and DNA modification enzymes occurs owing to metabolic reprogramming driven by oncogenes and expression of metabolism-associated genes is, in turn, epigenetically regulated, promoting the well-known metabolic reprogramming of cancer cells and, consequently, altering the metabolome. Thus, several malignant traits are supported by the interplay between metabolomics and epigenetics, promoting neoplastic transformation. In this review we emphasize the importance of tumour metabolites in the activity of most chromatin-modifying enzymes and implication in neoplastic transformation. Furthermore, candidate targets deriving from metabolism of cancer cells and altered epigenetic factors is emphasized, focusing on compounds that counteract the epigenomic-metabolic interplay in cancer

Delivery of miR-200c-3p Using Tumor-Targeted Mesoporous Silica Nanoparticles for Breast Cancer Therapy

[EN] Despite advancesin breast cancer treatment, it remainsthe leadingcause of cancer-related death in women worldwide. In this context,microRNAs have emerged as potential therapeutic targets but stillpresent some limitations for in vivo applications.Particularly, miR-200c-3p is a well-known tumor suppressor microRNAthat inhibits tumor progression and metastasis in breast cancer throughdownregulating ZEB1 and ZEB2. Basedon the above, we describe the design and validation of a nanodeviceusing mesoporous silica nanoparticles for miR-200c-3p delivery forbreast cancer treatment. We demonstrate the biocompatibility of thesynthesized nanodevices as well as their ability to escape from endosomes/lysosomesand inhibit tumorigenesis, invasion, migration, and proliferationof tumor cells in vitro. Moreover, tumor targetingand effective delivery of miR-200c-3p from the nanoparticles in vivo are confirmed in an orthotopic breast cancer mousemodel, and the therapeutic efficacy is also evidenced by a decreasein tumor size and lung metastasis, while showing no signs of toxicity.Overall, our results provide evidence that miR-200c-3p-loaded nanoparticlesare a potential strategy for breast cancer therapy and a safe andeffective system for tumor-targeted delivery of microRNAs.This research was supported by project PID2021-126304OB-C41 funded by MCIN/AEI/10.13039/501100011033/ and by European Regional Development Fund A way of doing Europe. Also, this study forms part of the Advanced Materials program (MFA/2022/049) and was supported by MCIN with funding from European Union NextGeneration EU(PRTR-C17.I1) and by Generalitat Valenciana. This study was also supported by Generalitat Valenciana (CIPROM/2021/007). This research was also supported by CIBER Consorcio Centro de Investigación Biomédica en Red CIBER-BBN(CB07/01/2012), CIBERONC(CB16/12/00481), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación. This work was also supported by Spanish Government and cofinanced by FEDER Funds (PI18/01219, PI21/01351) .I.G.-C. was funded by Margarita Salas post doctoral grant (European Union-Nextgeneration EU). A.A.-A. and A.L. were funded by Asociación Española Contra el Cancer.J.F.B. was funded by Instituto de Salud Carlos III and the European Social Fund for the financial support 'Sara Borrell' (CD19/00038). V.C.-N. was funded by Ministerio de Ciencia e Innovacio¿n (FPU grant), and J.M.C. was funded by Sociedad Española de Oncología Médica (Río Hortega-SEOM)Garrido-Cano, I.; Adam-Artigues, A.; Lameirinhas, A.; Blandez, JF.; Candela-Noguera, V.; Lluch, A.; Bermejo, B.... (2023). Delivery of miR-200c-3p Using Tumor-Targeted Mesoporous Silica Nanoparticles for Breast Cancer Therapy. ACS Applied Materials & Interfaces. 15(32):38323-38334. https://doi.org/10.1021/acsami.3c075413832338334153

Sirtuins’ deregulation in bladder cancer: SIRT7 is implicated in tumor progression through epithelial to mesenchymal transition promotion

Sirtuins are emerging players in cancer biology and other age-related disorders, and their putative role in bladder cancer (BlCa) remains elusive. Further understanding of disease biology may allow for generation of more effective pathway-based biomarkers and targeted therapies. Herein, we aimed to illuminate the role of sirtuins’ family in BlCa and evaluate their potential as disease biomarkers and therapeutic targets. SIRT1-7 transcripts and protein levels were evaluated in a series of primary BlCa and normal bladder mucosa tissues. SIRT7 knockdown was performed through lentiviral transduction in MGHU3, 5637 and J82 cells and its functional role was assessed. SIRT1, 2, 4 and 5 expression levels were significantly lower in BlCa, whereas SIRT6 and 7 were overexpressed, and these results were corroborated by TCGA cohort analysis. SIRT7 transcript levels were significantly decreased in muscle-invasive vs. papillary BlCa. In vitro studies showed that SIRT7 downregulation promoted cells migration and invasion. Accordingly, increased EMT markers expression and decreased E-Cadherin (CDH1) was observed in those BlCa cells. Moreover, increased EZH2 expression and H3K27me3 deposition in E-Cadherin promoter was found in sh-SIRT7 cells. We demonstrated that sirtuins are globally deregulated in BlCa, and specifically SIRT7 downregulation is implicated in EMT, fostering BlCa invasiveness through EZH2-CDH1 axis.This research was supported by the Research Center of the Portuguese Oncology Institute of Porto (CI-IPOP–FBGEBC-27 and PI 74-CI-IPOP-19-2016), by Fundação para a Ciência e Tecnologia (FCT) (PhD fellowships SFRH/BD/112673/2015 to S.M.-R and SFRH/BD/92786/2013 to C.S.G.; IF/00601/2012 to B.M.C.), and by Fundo Europeu de Desenvolvimento Regional (FEDER) (post-doctoral fellowships IPO/ESTIMANORTE01-0145-FEDER-000027 to V.M.-G. and COMPETE/FEDER/FCT_CI-IPOP-BPD/UID/DTP/00776/2013 to I.G.)

Dissolvable Carboxymethylcellulose Microneedles for Noninvasive and Rapid Administration of Diclofenac Sodium

The aim of this study is to prepare dissolvable biopolymeric microneedle (MN) patches composed solely of sodium carboxymethylcellulose (CMC), a water-soluble cellulose derivative with good film-forming ability, by micromolding technology for the transdermal delivery of diclofenac sodium salt (DCF). The MNs with ≈456 µm in height displayed adequate morphology, thermal stability up to 200 °C, and the required mechanical strength for skin insertion (>0.15 N needle−1). Experiments in ex vivo abdominal human skin demonstrate the insertion capability of the CMC_DCF MNs up to 401 µm in depth. The dissolution of the patches in saline buffer results in a maximum cumulative release of 98% of diclofenac after 40 min, and insertion in a skin simulant reveals that all MNs completely dissolve within 10 min. Moreover, the MN patches are noncytotoxic toward human keratinocytes. These results suggest that the MN patches produced with CMC are promising biopolymeric systems for the rapid administration of DCF in a minimally invasive manner.publishe

The Complex Interplay between Metabolic Reprogramming and Epigenetic Alterations in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common malignancy affecting the kidney. Current therapies are mostly curative for localized disease, but do not completely preclude recurrence and metastization. Thus, it is imperative to develop new therapeutic strategies based on RCC biological properties. Presently, metabolic reprograming and epigenetic alterations are recognized cancer hallmarks and their interactions are still in its infancy concerning RCC. In this review, we explore RCC biology, highlighting genetic and epigenetic alterations that contribute to metabolic deregulation of tumor cells, including high glycolytic phenotype (Warburg effect). Moreover, we critically discuss available data concerning epigenetic enzymes’ regulation by aberrant metabolite accumulation and their consequences in RCC emergence and progression. Finally, we emphasize the clinical relevance of uncovering novel therapeutic targets based on epigenetic reprograming by metabolic features to improve treatment and survival of RCC patients

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Background: Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms’ regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate’s impact on epigenome regulation of highly glycolytic tumors might allow for new therapeutic strategies. Herein, we investigated how extracellular lactate affected sirtuin 1 activity, a class III histone deacetylase (sirtuins, SIRTs) in RCC. Methods: In vitro and in vivo interactions between lactate and SIRT1 in RCC were investigated in normal kidney and RCC cell lines. Finally, SIRT1 and N-cadherin immunoexpression was assessed in human RCC and normal renal tissues. Results: Lactate inhibited SIRT1 expression in normal kidney and RCC cells, increasing global H3 and H3K9 acetylation. Cells exposed to lactate showed increased cell migration and invasion entailing a mesenchymal phenotype. Treatment with a SIRT1 inhibitor, nicotinamide (NAM), paralleled lactate effects, promoting cell aggressiveness. In contrast, alpha-cyano-4-hydroxycinnamate (CHC), a lactate transporter inhibitor, reversed them by blocking lactate transport. In vivo (chick chorioallantoic membrane (CAM) assay), lactate and NAM exposure were associated with increased tumor size and blood vessel recruitment, whereas CHC displayed the opposite effect. Moreover, primary RCC revealed N-cadherin upregulation whereas SIRT1 expression levels were downregulated compared to normal tissues. Conclusions: In RCC, lactate enhanced aggressiveness and modulated normal kidney cell phenotype, in part through downregulation of SIRT1, unveiling tumor metabolism as a promising therapeutic target

Role of SALL4 in HER2+ Breast Cancer Progression: Regulating PI3K/AKT Pathway

Treatment for the HER2+ breast cancer subtype is still unsatisfactory, despite breakthroughs in research. The discovery of various new molecular mechanisms of transcription factors may help to make treatment regimens more effective. The transcription factor SALL4 has been related to aggressiveness and resistance therapy in cancer. Its molecular mechanisms and involvement in various signaling pathways are unknown in the HER2+ breast cancer subtype. In this study, we have evaluated the implication of SALL4 in the HER2+ subtype through its expression in patients’ samples and gain and loss of function in HER2+ cell lines. We found higher SALL4 expression in breast cancer tissues compared to healthy tissue. Interestingly, high SALL4 expression was associated with disease relapse and poor patient survival. In HER2+ cell lines, transient overexpression of SALL4 modulates PI3K/AKT signaling through regulating PTEN expression and BCL2, which increases cell survival and proliferation while reducing the efficacy of trastuzumab. SALL4 has also been observed to regulate the epithelial–mesenchymal transition and stemness features. SALL4 overexpression significantly reduced the epithelial markers E-cadherin, while it increased the mesenchymal markers β-catenin, vimentin and fibronectin. Furthermore, it has been also observed an increased expression of MYC, an essential transcription factor for regulating epithelial-mesenchymal transition and/or cancer stem cells. Our study demonstrates, for the first time, the importance of SALL4 in the HER2+ subtype and partial regulation of trastuzumab sensitivity. It provides a viable molecular mechanism-driven therapeutic strategy for an important subset of HER2-overexpressing patients whose malignancies are mediated by SALL4 expression

Clinical Impact of New Treatment Strategies for HER2-Positive Metastatic Breast Cancer Patients with Resistance to Classical Anti-HER Therapies

HER2-positive breast cancer accounts for 15–20% of all breast cancer cases. This subtype is characterized by an aggressive behavior and poor prognosis. Anti-HER2 therapies have considerably improved the natural course of the disease. Despite this, relapse still occurs in around 20% of patients due to primary or acquired treatment resistance, and metastasis remains an incurable disease. This article reviews the main mechanisms underlying resistance to anti-HER2 treatments, focusing on newer HER2-targeted therapies. The progress in anti-HER2 drugs includes the development of novel antibody–drug conjugates with improvements in the conjugation process and novel linkers and payloads. Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. The combination of anti-HER2 agents with other drugs is also being evaluated. The addition of immunotherapy checkpoint inhibitors shows some benefit in a subset of patients, indicating the need for useful biomarkers to properly stratify patients. Besides, CDK4/6 and tyrosine kinase inhibitors are also included in the design of new treatment strategies. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms