Application of advanced very high-resolution radiometer (AVHRR)-based vegetation health indices for modelling and predicting malaria in Northern Benin, West Africa.

BACKGROUND: Vegetation health (VH) is a powerful characteristic for forecasting malaria incidence in regions where the disease is prevalent. This study aims to determine how vegetation health affects the prevalence of malaria and create seasonal weather forecasts using NOAA/AVHRR environmental satellite data that can be substituted for malaria epidemic forecasts. METHODS: Weekly advanced very high-resolution radiometer (AVHRR) data were retrieved from the NOAA satellite website from 2009 to 2021. The monthly number of malaria cases was collected from the Ministry of Health of Benin from 2009 to 2021 and matched with AVHRR data. Pearson correlation was calculated to investigate the impact of vegetation health on malaria transmission. Ordinary least squares (OLS), support vector machine (SVM) and principal component regression (PCR) were applied to forecast the monthly number of cases of malaria in Northern Benin. A random sample of proposed models was used to assess accuracy and bias. RESULTS: Estimates place the annual percentage rise in malaria cases at 9.07% over 2009-2021 period. Moisture (VCI) for weeks 19-21 predicts 75% of the number of malaria cases in the month of the start of high mosquito activities. Soil temperature (TCI) and vegetation health index (VHI) predicted one month earlier than the start of mosquito activities through transmission, 78% of monthly malaria incidence. CONCLUSIONS: SVM model D is more effective than OLS model A in the prediction of malaria incidence in Northern Benin. These models are a very useful tool for stakeholders looking to lessen the impact of malaria in Benin.

The PRP19 Ubiquitin Ligase, Standing at the Cross-Roads of mRNA Processing and Genome Stability.

mRNA processing factors are increasingly being recognized as important regulators of genome stability. By preventing and resolving RNA:DNA hybrids that form co-transcriptionally, these proteins help avoid replication-transcription conflicts and thus contribute to genome stability through their normal function in RNA maturation. Some of these factors also have direct roles in the activation of the DNA damage response and in DNA repair. One of the most intriguing cases is that of PRP19, an evolutionarily conserved essential E3 ubiquitin ligase that promotes mRNA splicing, but also participates directly in ATR activation, double-strand break resection and mitosis. Here, we review historical and recent work on PRP19 and its associated proteins, highlighting their multifarious cellular functions as central regulators of spliceosome activity, R-loop homeostasis, DNA damage signaling and repair and cell division. Finally, we discuss open questions that are bound to shed further light on the functions of PRP19-containing complexes in both normal and cancer cells.

The Functions of the Demethylase JMJD3 in Cancer.

Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the tri methylation of lysine from histone 3 (H3K27me3) mark, a repressive epigenetic mark often under- or overexpressed in a wide range of cancers. Two actors regulate H3K27 methylation: Jumonji Domain-Containing Protein 3 demethylase (JMJD3) and Enhancer of zeste homolog 2 (EZH2) methyltransferase. A number of studies have highlighted the deregulation of these actors, which is why this scientific review will focus on the role of JMJD3 and, consequently, H3K27me3 in cancer development. Data on JMJD3's involvement in cancer are classified by cancer type: nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, and gastric cancers.

TIP60/P400/H4K12ac Plays a Role as a Heterochromatin Back-up Skeleton in Breast Cancer.

BACKGROUND/AIM: In breast cancer, initiation of carcinogenesis leads to epigenetic dysregulation, which can lead for example to the loss of the heterochromatin skeleton SUV39H1/H3K9me3/HP1 or the supposed secondary skeleton TIP60/P400/H4K12ac/BRD (2/4), which allows the maintenance of chromatin integrity and plasticity. This study investigated the relationship between TIP60, P400 and H4K12ac and their implications in breast tumors. MATERIALS AND METHODS: Seventy-seven patients diagnosed with breast cancer were included in this study. Chromatin immunoprecipitation (ChIP) assay was used to identify chromatin modifications. Western blot and reverse transcription and quantitative real-time PCR were used to determine protein and gene expression, respectively. RESULTS: We verified the variation in H4K12ac enrichment and the co-localization of H4K12ac and TIP60 on the euchromatin and heterochromatin genes, respectively, by ChIP-qPCR and ChIP-reChIP, which showed an enrichment of H4K12ac on specific genes in tumors compared to the adjacent healthy tissue and a co-localization of H4K12ac with TIP60 in different breast tumor types. Furthermore, RNA and protein expression of TIP60 and P400 was investigated and overexpression of TIP60 and P400 mRNA was associated with tumor aggressiveness. CONCLUSION: There is a potential interaction between H4K12ac and TIP60 in heterochromatin or euchromatin in breast tumors.

Digging Deeper into Breast Cancer Epigenetics: Insights from Chemical Inhibition of Histone Acetyltransferase TIP60 In Vitro.

Breast cancer is often sporadic due to several factors. Among them, the deregulation of epigenetic proteins may be involved. TIP60 or KAT5 is an acetyltransferase that regulates gene transcription through the chromatin structure. This pleiotropic protein acts in several cellular pathways by acetylating proteins. RNA and protein expressions of TIP60 were shown to decrease in some breast cancer subtypes, particularly in triple-negative breast cancer (TNBC), where a low expression of TIP60 was exhibited compared with luminal subtypes. In this study, the inhibition of the residual activity of TIP60 in breast cancer cell lines was investigated by using two chemical inhibitors, TH1834 and NU9056, first on the acetylation of the specific target, lysine 4 of histone 3 (H3K4) by immunoblotting, and second, by chromatin immunoprecipitation (ChIP)-qPCR (-quantitative Polymerase Chain Reaction). Subsequently, significant decreases or a trend toward decrease of H3K4ac in the different chromatin compartments were observed. In addition, the expression of 48 human nuclear receptors was studied with TaqMan Low-Density Array in these breast cancer cell lines treated with TIP60 inhibitors. The statistical analysis allowed us to comprehensively characterize the androgen receptor and NR3C2 receptors in TNBC cell lines after TH1834 or NU9056 treatment. The understanding of the residual activity of TIP60 in the evolution of breast cancer might be a major asset in the fight against this disease, and could allow TIP60 to be used as a biomarker or therapeutic target for breast cancer progression in the future.

Epi-drugs as triple-negative breast cancer treatment.

Triple-negative breast cancer (TNBC) types with poor prognosis are due to the absence of estrogen receptors, progesterone receptors and HEGFR-2. The lack of suitable therapy for TNBC has led the research community to turn toward epigenetic regulation and its protagonists that can modulate certain oncogenes and tumor suppressors. This has opened an important new field of therapy using epi-drugs, in preclinical and clinical trials. The epi-drugs are natural or synthetic molecules capable of inhibiting or modulating the activity of epigenetic proteins such as DNA methyltransferases, modulating the expression of interferon microRNAs, as well as histone methyltransferases, demethylases, acetyltransferases and deacetylases. This review investigated the epi-drugs used in the treatment of TNBC.

Breaking down the Contradictory Roles of Histone Deacetylase SIRT1 in Human Breast Cancer.

Breast cancer (BC) is the most common type of cancer in women worldwide; it is a multifactorial genetic disease. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis and cancer metastasis in different types of human cancers, including breast cancer. Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC) that deacetylates both histone and non-histone targets. The often-described 'regulator of regulators' is deeply implicated in apoptosis, gene regulation, genome maintenance, DNA repair, aging, and cancer development. However, despite the accumulated studies over the past decade, the role of SIRT1 in human breast cancer remains a subject of debate and controversy. The ambiguity surrounding the implications of SIRT1 in breast tumorigenesis stems from the discrepancy between studies, which have shown both tumor-suppressive and promoting functions of SIRT1. Furthermore, studies have shown that SIRT1 deficiency promotes or suppresses tumors in breast cancer, making it an attractive therapeutic target in cancer treatment. This review provides a comprehensive examination of the various implications of SIRT1 in breast cancer development and metastasis. We will also discuss the mechanisms underlying the conflicting roles of SIRT1, as well as its selective modulators, in breast carcinogenesis.

TIP60: an actor in acetylation of H3K4 and tumor development in breast cancer.

AIM: The acetyltransferase TIP60 is reported to be downregulated in several cancers, in particular breast cancer, but the molecular mechanisms resulting from its alteration are still unclear. MATERIALS & METHODS: In breast tumors, H3K4ac enrichment and its link with TIP60 were evaluated by chromatin immunoprecipitation-qPCR and re-chromatin immunoprecipitation techniques. To assess the biological roles of TIP60 in breast cancer, two cell lines of breast cancer, MDA-MB-231 (ER-) and MCF-7 (ER+) were transfected with shRNA specifically targeting TIP60 and injected to athymic Balb-c mice. RESULTS: We identified a potential target of TIP60, H3K4. We show that an underexpression of TIP60 could contribute to a reduction of H3K4 acetylation in breast cancer. An increase in tumor development was noted in sh-TIP60 MDA-MB-231 xenografts and a slowdown of tumor growth in sh-TIP60 MCF-7 xenografts. CONCLUSION: This is evidence that the underexpression of TIP60 observed in breast cancer can promote the tumorigenesis of ER-negative tumors.

SIRT1-dependent epigenetic regulation of H3 and H4 histone acetylation in human breast cancer.

Breast cancer is the most frequently diagnosed malignancy in women worldwide. It is well established that the complexity of carcinogenesis involves profound epigenetic deregulations that contribute to the tumorigenesis process. Deregulated H3 and H4 acetylated histone marks are amongst those alterations. Sirtuin-1 (SIRT1) is a class-III histone deacetylase deeply involved in apoptosis, genomic stability, gene expression regulation and breast tumorigenesis. However, the underlying molecular mechanism by which SIRT1 regulates H3 and H4 acetylated marks, and consequently cancer-related gene expression in breast cancer, remains uncharacterized. In this study, we elucidated SIRT1 epigenetic role and analyzed the link between the latter and histones H3 and H4 epigenetic marks in all 5 molecular subtypes of breast cancer. Using a cohort of 135 human breast tumors and their matched normal tissues, as well as 5 human-derived cell lines, we identified H3k4ac as a new prime target of SIRT1 in breast cancer. We also uncovered an inverse correlation between SIRT1 and the 3 epigenetic marks H3k4ac, H3k9ac and H4k16ac expression patterns. We showed that SIRT1 modulates the acetylation patterns of histones H3 and H4 in breast cancer. Moreover, SIRT1 regulates its H3 acetylated targets in a subtype-specific manner. Furthermore, SIRT1 siRNA-mediated knockdown increases histone acetylation levels at 6 breast cancer-related gene promoters: AR, BRCA1, ERS1, ERS2, EZH2 and EP300. In summary, this report characterizes for the first time the epigenetic behavior of SIRT1 in human breast carcinoma. These novel findings point to a potential use of SIRT1 as an epigenetic therapeutic target in breast cancer.

A new metabolic gene signature in prostate cancer regulated by JMJD3 and EZH2.

Histone methylation is essential for gene expression control. Trimethylated lysine 27 of histone 3 (H3K27me3) is controlled by the balance between the activities of JMJD3 demethylase and EZH2 methyltransferase. This epigenetic mark has been shown to be deregulated in prostate cancer, and evidence shows H3K27me3 enrichment on gene promoters in prostate cancer. To study the impact of this enrichment, a transcriptomic analysis with TaqMan Low Density Array (TLDA) of several genes was studied on prostate biopsies divided into three clinical grades: normal (n = 23) and two tumor groups that differed in their aggressiveness (Gleason score ≤ 7 (n = 20) and >7 (n = 19)). ANOVA demonstrated that expression of the gene set was upregulated in tumors and correlated with Gleason score, thus discriminating between the three clinical groups. Six genes involved in key cellular processes stood out: JMJD3, EZH2, MGMT, TRA2A, U2AF1 and RPS6KA2. Chromatin immunoprecipitation demonstrated collocation of EZH2 and JMJD3 on gene promoters that was dependent on disease stage. Gene set expression was also evaluated on prostate cancer cell lines (DU 145, PC-3 and LNCaP) treated with an inhibitor of JMJD3 (GSK-J4) or EZH2 (DZNeP) to study their involvement in gene regulation. Results showed a difference in GSK-J4 sensitivity under PTEN status of cell lines and an opposite gene expression profile according to androgen status of cells. In summary, our data describe the impacts of JMJD3 and EZH2 on a new gene signature involved in prostate cancer that may help identify diagnostic and therapeutic targets in prostate cancer.

Dual SIRT1 expression patterns strongly suggests its bivalent role in human breast cancer.

Breast cancer is the most common cancer in women, and the leading cause of cancer death in women worldwide. SIRT1 (silent mating type information regulation 2 homolog) 1 is a class-III histone deacetylase involved in apoptosis regulation, DNA repair and tumorigenesis. However, its role in breast carcinoma remains controversial, as both tumor-suppressive and tumor-promoting functions have been reported. Also, there are very few reports available where expression of SIRT1 is comprehensively analyzed in breast tumors classified by molecular subtype. Here, using a cohort of 50 human breast tumors and their matched normal tissues, we investigated SIRT1 expression levels in the 5 molecular subtypes of breast cancer according to the St Gallen classification (2013). Tumors and their corresponding normal tissue samples were collected from all patients, and SIRT1 mRNA and protein expression levels were then examined by real-time quantitative polymerase chain reaction and immunoblotting, respectively. After statistical analysis, the results showed a dual expression profile of SIRT1 in human breast carcinoma, with significant overexpression in luminal and HER2-enriched subtypes and significantly reduced expression in the triple-negative subtype. We also found an inverse correlation between SIRT1 expression and breast cancer aggressivity. These novel findings suggest that SIRT1 plays a dual role in breast tumors depending on its expression rate and the molecular subtype of the cancer. Our data also point to a potential role for SIRT1 as a prognostic biomarker in breast cancer.