Aberrant glycosylation of glycoproteins has been linked with various pathologies. Therefore, understanding the relationship between aberrant glycosylation patterns and the onset and progression of the disease is an important research goal that may provide insights into cancer diagnosis and new therapy development. In this study, we use a surface plasmon resonance imaging biosensor and a lectin array to investigate aberrant glycosylation patterns associated with oncohematological disease-myelodysplastic syndromes (MDS). In particular, we detected the interaction between the lectins and glycoproteins present in the blood plasma of patients (three MDS subgroups with different risks of progression to acute myeloid leukemia (AML) and AML patients) and healthy controls. The interaction with lectins from Aleuria aurantia (AAL) and Erythrina cristagalli was more pronounced for plasma samples of the MDS and AML patients, and there was a significant difference between the sensor response to the interaction of AAL with blood plasma from low and medium-risk MDS patients and healthy controls. Our data also suggest that progression from MDS to AML is accompanied by sialylation of glycoproteins and increased levels of truncated O-glycans and that the number of lectins that allow discriminating different stages of disease increases as the disease progresses.

• MeSH
• Leukemia, Myeloid, Acute * MeSH
• Biosensing Techniques * MeSH
• Glycoproteins metabolism   MeSH
• Glycosylation MeSH
• Plasma metabolism   MeSH
• Lectins MeSH
• Humans MeSH
• Myelodysplastic Syndromes * therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glycoproteins MeSH
• Lectins MeSH

Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (SBSN). Originally described as a component of the cornified envelope, the function of stratified epithelia-expressed SBSN is unknown. Both the lack of knowledge about the gene role under physiological conditions and the emerging link of SBSN to various human diseases, including cancer, attract research interest. The association of SBSN expression with poor prognosis of patients suffering from oesophageal carcinoma, glioblastoma multiforme, and myelodysplastic syndromes suggests that SBSN may play a role in human tumourigenesis. Three SBSN isoforms code for the secreted proteins with putative function as signalling molecules, yet with poorly described effects. In this first review about SBSN, we summarised the current knowledge accumulated since its original description, and we discuss the potential mechanisms and roles of SBSN in both physiology and pathology.

• Keywords
• MAPK signalling, cancer resistance, cancer stem-like cells, immunity, interferon, suprabasin,
• MeSH
• Antigens, Differentiation * genetics   metabolism   MeSH
• Carcinogenesis * genetics   metabolism   MeSH
• Humans MeSH
• Neoplasm Proteins * genetics   metabolism   MeSH
• Neoplasms * genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Antigens, Differentiation * MeSH
• Neoplasm Proteins * MeSH
• SBSN protein, human MeSH Browser

Myelodysplastic syndromes (MDS) are preleukemic disorders characterized by clonal growth of mutant hematopoietic stem and progenitor cells. MDS are associated with proinflammatory signaling, dysregulated immune response, and cell death in the bone marrow (BM). Aging, autoinflammation and autoimmunity are crucial features of disease progression, concordant with promoting growth of malignant clones and accumulation of mutations. Suprabasin (SBSN), a recently proposed proto-oncogene of unknown function, physiologically expressed in stratified epithelia, is associated with poor prognosis of several human malignancies. Here, we showed that SBSN is expressed in the BM by myeloid cell subpopulations, including myeloid-derived suppressor cells, and is secreted into BM plasma and peripheral blood of MDS patients. The highest expression of SBSN was present in a patient group with poor prognosis. SBSN levels in the BM correlated positively with blast percentage and negatively with CCL2 chemokine levels and lymphocyte count. In vitro treatment of leukemic cells with interferon-gamma and demethylating agent 5-azacytidine (5-AC) induced SBSN expression. This indicated that aberrant cytokine levels in the BM and epigenetic landscape modifications in MDS patients may underlie ectopic expression of SBSN. Our findings suggest SBSN as a candidate biomarker of high-risk MDS with a possible role in disease progression and therapy resistance.

• Keywords
• 5-azacytidine, MDS, MDSCs, biomarker, suprabasin,
• MeSH
• Azacitidine pharmacology   MeSH
• Biomarkers blood   metabolism   MeSH
• Chemokine CCL2 metabolism   MeSH
• Antigens, Differentiation blood   genetics   metabolism   MeSH
• HEK293 Cells MeSH
• Interferon-gamma pharmacology   MeSH
• Cell Compartmentation drug effects   MeSH
• Bone Marrow metabolism   MeSH
• Leukocytes, Mononuclear metabolism   MeSH
• Humans MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Myelodysplastic Syndromes blood   metabolism   MeSH
• Myeloid Cells drug effects   metabolism   MeSH
• Cell Line, Tumor MeSH
• Neoplasm Proteins blood   genetics   metabolism   MeSH
• Lymphocyte Count MeSH
• Prognosis MeSH
• Proto-Oncogene Mas MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Azacitidine MeSH
• Biomarkers MeSH
• Chemokine CCL2 MeSH
• Antigens, Differentiation MeSH
• Interferon-gamma MeSH
• MAS1 protein, human MeSH Browser
• RNA, Messenger MeSH
• Neoplasm Proteins MeSH
• Proto-Oncogene Mas MeSH
• SBSN protein, human MeSH Browser

Wild type mitochondrial isocitrate dehydrogenase (IDH2) was previously reported to produce oncometabolite 2-hydroxyglutarate (2HG). Besides, mitochondrial deacetylase SIRT3 has been shown to regulate the oxidative function of IDH2. However, regulation of 2HG formation by SIRT3-mediated deacetylation was not investigated yet. We aimed to study mitochondrial IDH2 function in response to acetylation and deacetylation, and focus specifically on 2HG production by IDH2. We used acetylation surrogate mutant of IDH2 K413Q and assayed enzyme kinetics of oxidative decarboxylation of isocitrate, 2HG production by the enzyme, and 2HG production in cells. The purified IDH2 K413Q exhibited lower oxidative reaction rates than IDH2 WT. 2HG production by IDH2 K413Q was largely diminished at the enzymatic and cellular level, and knockdown of SIRT3 also inhibited 2HG production by IDH2. Contrary, the expression of putative mitochondrial acetylase GCN5L likely does not target IDH2. Using mass spectroscopy, we further identified lysine residues within IDH2, which are the substrates of SIRT3. In summary, we demonstrate that 2HG levels arise from non-mutant IDH2 reductive function and decrease with increasing acetylation level. The newly identified lysine residues might apply in regulation of IDH2 function in response to metabolic perturbations occurring in cancer cells, such as glucose-free conditions.

• MeSH
• Acetylation MeSH
• Glutarates metabolism   MeSH
• Isocitrate Dehydrogenase genetics   metabolism   MeSH
• Isocitrates chemistry   MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Cell Line, Tumor MeSH
• NADP metabolism   MeSH
• Oxidation-Reduction MeSH
• Nerve Tissue Proteins metabolism   MeSH
• Sirtuin 3 metabolism   MeSH
• Gene Silencing MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• alpha-hydroxyglutarate MeSH Browser
• BLOC1S1 protein, human MeSH Browser
• Glutarates MeSH
• IDH2 protein, human MeSH Browser
• Isocitrate Dehydrogenase MeSH
• Isocitrates MeSH
• isocitric acid MeSH Browser
• NADP MeSH
• Nerve Tissue Proteins MeSH
• SIRT3 protein, human MeSH Browser
• Sirtuin 3 MeSH