Anti-Leukemia Activity of MS-275 Histone Deacetylase Inhibitor Implicates 4-1BBL/4-1BB Immunomodulatory Functions

Histone deacetylase inhibitors (HDACi) have demonstrated promising therapeutic potential in clinical trials for hematological malignancies. HDACi, such as SAHA/Vorinostat, Trichostatin A, and MS-275 were found to induce apoptosis of leukemic blasts through activation of the death receptor pathway and transcriptional induction of the Tumor Necrosis Factor (TNF)-related pro-apoptotic family members, TRAIL and FasL. The impact of HDACi on TNF-related costimulatory molecules such as 4-1BB ligand (4-1BBL/TNFSF9) is however not known. Following exposure to SAHA/Vorinostat, Trichostatin A, and MS-275, transcript levels were determined by real time PCR in Jurkat, Raji and U937 cells. Treatment with HDACi up-regulated TNFSF9 gene expression in the three leukemia cell lines, yet to different extend and with distinct kinetics, which did not require de novo protein synthesis and was not associated with DNAse I hypersensitive chromatin remodeling. Transcriptional activity of TNFSF9 promoter-luciferase constructs was induced up to 12 fold by HDACi, and implication of Sp1/Sp3 transcription factors binding to functional GC-box elements was evidenced by reporter gene assays, site-directed mutagenesis, and electrophoretic mobility shift assays. Functionality of modulated target genes was assessed in allogeneic mixed leukocyte reaction experiments. MS-275- and to a lesser extent Trichostatin A- and SAHA-treated Raji cells significantly up regulated T lymphocytes proliferation which was reduced by about 50% by a 4-1BB blocking recombinant protein, while MS-275- but neither Trichostatin A- nor SAHA-treated cells up-regulated IFNγ secretion by T lymphocytes. Our results identify 4-1BBL/4-1BB as a downstream target of HDACi, especially of MS-275 anti-leukemia action in vitro. Thus, HDACi such as MS-275 displaying dual TNF-dependent proapoptotic and costimulatory activities might be favored for inclusion in HDACi-based anti-cancer therapeutic strategies

hPG80 (circulating progastrin) as a blood biomarker for high-grade glial tumors: A pilot study

International audienceCurrently, the long-term prognosis and survival rate of patients with high-grade glial tumors remains poor and there are no biomarkers. hPG 80 (circulating progastrin) secreted into the blood by tumor cells has been widely studied in colorectal cancer. Its involvement in tumorigenesis has been demonstrated in the literature. Moreover, according to a recent study, hPG 80 is expressed in the blood of cancer patients at a significantly higher concentration than in the control group composed of healthy blood donors.The PROGLIO study is a pilot, single-center, longitudinal study that primarily seeks to evaluate circulating plasma hPG 80 concentrations over time in patients with high-grade glial tumors. A fasting blood sample will be taken on the start and end day of radiotherapy and during the adjuvant chemotherapy (every 3 cycles). Follow-up monitoring will be performed for 9 months, with a blood sample taken every 3 months on the day of the follow-up MRI. The study plans to recruit 30 patients and recruitment started in February 2022. Trial registration ClinicalTrials.gov , ID NCT05157594; registered on October 27, 2021

Active transcription of human TNFSF/CD95L and TNFSF14/Light genes involves distinct mechanisms of chromatin remodeling

info:eu-repo/semantics/publishe

Plasma hPG80 (Circulating Progastrin) as a Novel Prognostic Biomarker for early-stage breast cancer in a breast cancer cohort

Abstract Background Recurrence and metastases are still frequent outcomes after initial tumour control in women diagnosed with breast cancer. Although therapies are selected based on tumour characteristics measured at baseline, prognostic biomarkers can identify those at risk of poor outcomes. Circulating progastrin or hPG80 was found to be associated with survival outcomes in renal and hepatocellular carcinomas and was a plausible prognostic biomarker for breast cancer. Methods Women with incident breast cancers from Calgary, Alberta, Canada enrolled in the Breast to Bone (B2B) study between 2010 to 2016 and provided blood samples prior to any treatment initiation. Plasma from these baseline samples were analysed for circulating progastrin or hPG80. Participant characteristics as well as tumour ones were evaluated for their association with hPG80 and survival outcomes (time to recurrence, recurrence – free survival, breast cancer specific survival and overall survival) in Cox proportional hazards regression models. Results The 464 participants with measurable hPG80 in this study had an average age of 57.03 years (standard deviation of 11.17 years) and were predominantly diagnosed with Stage I (52.2%) and Stage II (40.1%) disease. A total of 50 recurrences and 50 deaths were recorded as of June 2022. In Cox PH regression models adjusted for chemotherapy, radiation therapy, cancer stage and age at diagnosis, log hPG80 (pmol/L) significantly increased the risks for recurrence (Hazard Ratio (HR) = 1.330, 95% Confidence Interval (CI) = (0.995 – 1.777, p = 0.054)), recurrence-free survival (HR = 1.399, 95% CI = (1.106 – 1.770), p = 0.005) and overall survival (HR = 1.385, 95% CI = (1.046 – 1.834), = 0.023) but not for breast cancer specific survival (HR = 1.015, 95% CI = (0.684 – 1.505), p = 0.942). Conclusions hPG80 levels measured at diagnosis were significantly associated with the risk of recurrence or death from any cause in women with breast cancer. Since the recurrence rates of breast cancer are still relatively high amongst women diagnosed at an early stage, identifying women at high risk of recurrence at their time of diagnosis is important. hPG80 is a promising new prognostic biomarker that could improve the identification of women at higher risk of poor outcomes

Régulation transcriptionnelle différentielle de la superfamille du TNF (rôle de la chromatine et contrôle pharmacologique à visée thérapeutique)

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Deacetylase inhibitors as candidate drugs to purge latently HIV-1-infected reservoirs in HAART patients? Mechanistic insights into regulation of viral replication by Deacetylase inhibitors

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Deacetylase inhibitors as candidate drugs to purge latently HIV-1-infected reservoirs in HAART patients? Mechanistic insights into regulation of viral replication by Deacetylase inhibitors

info:eu-repo/semantics/publishe

Primers used for Electrophoretic Mobility Shift Assays.

<p>(Only forward primers are indicated).</p

Modulation of <i>TNFSF9</i> transcript levels by HDACi does not require <i>de novo</i> protein synthesis and does not require <i>TNFSF9</i> promoter region chromatin remodeling.

<p>Jurkat JA16 cells were left unstimulated (UN) or were incubated for 1 hour with CHX (10 µg/ml) and then treated for 8 hours by TSA (250 nM), MS-275 (1 µM) and SAHA (1 µM). Total mRNA was extracted and transcripts of <i>TNFSF9</i> and <i>GAPDH</i> were analysed by PCR (A) and quantified by real-time PCR (B) as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007085#pone-0007085-g001" target="_blank">Fig. 1</a>. (C) Nuclei from Jurkat T cells left unstimulated (UN), or treated with TSA (500 nM) for 18 hours, were digested <i>in vivo</i> with increasing amounts of DNase I (0, 30, 40, 50, 60 and 70 U/ml) followed by <i>Sac</i>I digestion <i>in vitro</i> and indirect end-labeling (lower panel). The schematic organization of the <i>TNFSF9</i> locus, showing the indirect end-labeling and southern blotting strategy, as well as the DNaseI hypersensitive sites (DHS) identified in the course of the present study are depicted in the upper panel. The position of the probe used for the southern blotting, as well as the <i>TNFSF9</i> exon 1-3 are showed. Hypersensitive regions DHSI and DHSII are shown on the left. Molecular weight markers (MM) are a double digest of naked DNA by <i>Sac</i>I (12641 bp), <i>Nsi</i>I (9180 bp), <i>Nhe</i>I (6850 bp), <i>Hinc</i>II (5006 bp), <i>Xho</i>I (2390 bp) and <i>Bgl</i>II (1918 bp).</p

List of genes included in the quantitative RT-PCR low-density array.

<p>List of genes included in the quantitative RT-PCR low-density array.</p