Intricate ribosome composition and translational reprogramming in epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) involves profound changes in cell morphology, driven by transcriptional and epigenetic reprogramming. However, evidence suggests that translation and ribosome composition also play key roles in establishing pathophysiological phenotypes. Using genome-wide analyses, we reported significant rearrangement of the translational landscape and machinery during EMT.

Targeting sphingolipid metabolism in chronic lymphocytic leukemia.

Elevated levels of circulating C16:0 glucosylceramides (GluCer) and increased mRNA expression of UDP-glucose ceramide glycosyltransferase (UGCG), the enzyme responsible for converting ceramides (Cer) to GluCer, represent unfavorable prognostic markers in chronic lymphocytic leukemia (CLL) patients. To evaluate the therapeutic potential of inhibiting GluCer synthesis, we genetically repressed the UGCG pathway using in vitro models of leukemic B cells, in addition to UGCG pharmacological inhibition with approved drugs such as eliglustat and ibiglustat, both individually and in combination with ibrutinib, assessed in cell models and primary CLL patient cells. Cell viability, apoptosis, and proliferation were evaluated in vitro, and survival and apoptosis were examined ex vivo.

Non-canonical transcriptional regulation of the poor prognostic factor UGT2B17 in chronic lymphocytic leukemic and normal B cells.

Background: High expression of the glycosyltransferase UGT2B17 represents an independent adverse prognostic marker in chronic lymphocytic leukemia (CLL). It also constitutes a predictive marker for therapeutic response and a drug resistance mechanism. The key determinants driving expression of the UGT2B17 gene in normal and leukemic B-cells remain undefined.

Untargeted metabolomics identifies metabolic dysregulation of sphingolipids associated with aggressive chronic lymphocytic leukaemia and poor survival.

Background: Metabolic dependencies of chronic lymphocytic leukaemia (CLL) cells may represent new personalized treatment approaches in patients harbouring unfavourable features.

Methods: Here, we used untargeted metabolomics and lipidomics analyses to isolate metabolomic features associated with aggressive CLL and poor survival outcomes. We initially focused on profiles associated with overexpression of the adverse metabolic marker glycosyltransferase (UGT2B17) associated with poor survival and drug resistance.

A Non-Canonical Role for the Glycosyltransferase Enzyme UGT2B17 as a Novel Constituent of the B Cell Receptor Signalosome.

In chronic lymphocytic leukemia (CLL), an elevated glycosyltransferase UGT2B17 expression (UGT2B17) identifies a subgroup of patients with shorter survival and poor drug response. We uncovered a mechanism, possibly independent of its enzymatic function, characterized by an enhanced expression and signaling of the proximal effectors of the pro-survival B cell receptor (BCR) pathway and elevated Bruton tyrosine kinase (BTK) phosphorylation in B-CLL cells from UGT2B17 patients. A prominent feature of B-CLL cells is the strong correlation of UGT2B17 expression with the adverse marker ZAP70 encoding a tyrosine kinase that promotes B-CLL cell survival.

A liquid chromatography-mass spectrometry assay for the quantification of nucleotide sugars in human plasma and urine specimens and its clinical application.

Nucleotide sugars and more specifically UDP-sugars, represent a major source of energy, key components of extracellular matrix, glycosylation and glucuronidation reactions, and emerge as important signaling molecules through P2Y14 purinergic receptor. Despite their pivotal role in a variety of physiological and pathological processes and their potential as biomarkers, UDP-sugar composition of biological fluids remains poorly studied. We developed a liquid chromatography electrospray ionization tandem mass spectrometry in multiple reaction monitoring mode for the simultaneous quantification of UDP-glucose, UDP-galactose, UDP-glucuronic acid, UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine in human blood and urine.

Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer.

Background: A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated.

Erratum: Ribosomal RNA 2' O-methylation as a novel layer of inter-tumour heterogeneity in breast cancer.

[This corrects the article DOI: 10.1093/narcan/zcaa036.].

Ribosomal RNA 2'O-methylation as a novel layer of inter-tumour heterogeneity in breast cancer.

Recent epitranscriptomics studies unravelled that ribosomal RNA (rRNA) 2'O-methylation is an additional layer of gene expression regulation highlighting the ribosome as a novel actor of translation control. However, this major finding lies on evidences coming mainly, if not exclusively, from cellular models. Using the innovative next-generation RiboMeth-seq technology, we established the first rRNA 2'O-methylation landscape in 195 primary human breast tumours.

Iron and hepcidin mediate human colorectal cancer cell growth.

High dietary iron intake is a risk factor for the development of colorectal cancer. However, how iron subsequently impacts the proliferation of colorectal cancer cells remains unclear. This study determined the expression of six iron regulatory genes in twenty-one human colorectal cancer (CRC) biopsies and matched normal colonic tissue.

Analysis of the rRNA methylation complex components in pediatric B-cell precursor acute lymphoblastic leukemia: A pilot study.

Background: Dysregulation of ribosome biogenesis and alteration of ribosome composition, including alteration in ribosomal RNA (rRNA) 2'-O-ribose methylation, can play a role in malignant transformation and cancer progression. Several studies recently reported that components of the rRNA methylation complex are associated with leukemogenesis. However, no study ever investigated the alteration of ribosome biogenesis factors in the most common pediatric malignancy - B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Druggable Identifies Breast Tumours Associated with Poor Prognosis That Exhibit Different Biological Processes.

Nucleolin (NCL) is a multifunctional protein with oncogenic properties. Anti-NCL drugs show strong cytotoxic effects, including in triple-negative breast cancer (TNBC) models, and are currently being evaluated in phase II clinical trials. However, few studies have investigated the clinical value of and whether stratified cancer patients.

40 Years of Research Put p53 in Translation.

Since its discovery in 1979, p53 has shown multiple facets. Initially the tumor suppressor p53 protein was considered as a stress sensor able to maintain the genome integrity by regulating transcription of genes involved in cell cycle arrest, apoptosis and DNA repair. However, it rapidly came into light that p53 regulates gene expression to control a wider range of biological processes allowing rapid cell adaptation to environmental context.