Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics.

The NAD(+)-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6.

Chromosome 20 aberrations at the diploid-aneuploid transition in sporadic colorectal cancer.

DNA aneuploid sublines in sporadic colorectal cancers (CRCs) are quite frequent (about 85%) and likely the consequence of chromosomal instability and DNA copy number aberrations (CNAs). In order to gain insight into the mechanisms of the diploid-aneuploid transition in CRCs, we compared the CNA status in both diploid and aneuploid sublines. We used fresh/frozen material from 17 aneuploid CRCs, which was separated into 17 DNA diploid and 17 aneuploid sublines using enrichment of the epithelial component by multiparameter flow cytometry and sorting.

Human sirtuins: an overview of an emerging drug target in age-related diseases and cancer.

Sir2-like proteins (Sirtuins) are a class of enzymes conserved throughout the kingdoms of life. In fact, from Archaea to Mammals, these (class III) NAD+-dependent deacetylases catalyse the removal of the acetyl moiety from a substrate protein. Sirtuins show a conserved central catalytic domain with two more variable amino- and carboxy-terminal flanking regions.

Chromosomal aberrations and aneuploidy in oral potentially malignant lesions: distinctive features for tongue.

Background: The mucosae of the oral cavity are different at the histological level but appear all equally exposed to common genotoxic agents. As a result of this exposure, changes in the mucosal epithelia may develop giving rise to Oral Potentially Malignant Lesions (OPMLs), which with time may in turn progress to Oral Squamous Cell Carcinomas (OSCCs). Therefore, much effort should be devoted to identify features able to predict the likeliness of progression associated with an OPML.

Field effect in oral precancer as assessed by DNA flow cytometry and array-CGH.

Objective: 'Field cancerization' is an accepted model for oral carcinogenesis. So far, genetically altered fields have been just reported in the presence of carcinomas. This study assessed the distant mirror fields (MFs) of oral precancer by DNA high-resolution flow cytometry (hr DNA-FCM) and array-Comparative Genomic Hybridization (a-CGH).

Distinctive chromosomal instability patterns in oral verrucous and squamous cell carcinomas detected by high-resolution DNA flow cytometry.

Background: Oral verrucous carcinomas (OVCs) are characterized by better prognosis than oral squamous cell carcinomas (OSCCs). Because chromosomal instability (CIN) in solid tumors is indicative of prognosis, this study investigated whether OVCs and OSCCs were characterized by differences in CIN biomarkers.

Methods: Fresh or frozen multiple tissue samples were submitted to high-resolution DNA flow cytometry (hr DNA-FCM).

Oral cancer genesis and progression: DNA near-diploid aneuploidization and endoreduplication by high resolution flow cytometry.

Oral potentially malignant lesions (OPMLs) with dysplasia and aneuploidy are thought to have a high risk of progression into oral squamous cell carcinomas (OSCCs). Non-dysplastic "oral distant fields" (ODFs), characterized by clinically normal appearing mucosa sited at a distance from co-existing OPMLs, and non-dysplastic OPMLs may also represent an early pre-cancerous state. ODFs, OPMLs without and with dysplasia and OSCCs were investigated by high resolution DNA content flow cytometry (FCM).

Gene expression deregulation by KRAS G12D and G12V in a BRAF V600E context.

Background: KRAS and BRAF mutations appear of relevance in the genesis and progression of several solid tumor types but the co-occurrence and interaction of these mutations have not yet been fully elucidated. Using a microsatellite stable (MSS) colorectal cancer (CRC) cell line (Colo741) having mutated BRAF and KRASWT, we also aimed to investigate the KRAS-BRAF interaction. Gene expression profiles for control KRASWT, KRAS G12V and KRAS G12D transfected cells were obtained after cell clone selection and RT-PCR screening.

The C-terminal domain of the transcriptional corepressor CtBP is intrinsically unstructured.

C-terminal binding proteins (CtBPs) are moonlighting proteins involved in nuclear transcriptional corepression and in Golgi membrane tubule fission. Structural information on CtBPs is available for their substrate-binding domain, responsible for transcriptional repressor recognition/binding, and for the nucleotide-binding domain, involved in NAD(H)-binding and dimerization. On the contrary, little is known about the structure of CtBP C-terminal region ( approximately 90 residues), hosting sites for post-translational modifications.

GABP complex regulates transcription of eIF6 (p27BBP), an essential trans-acting factor in ribosome biogenesis.

Eukaryotic initiation factor 6 (eIF6, alias p27BBP) is required for the biogenesis of 60S ribosomal subunits. eIF6 expression levels are tightly regulated in vivo, where they correlate with cellular growth. We analyzed how transcriptional regulation of eIF6 is achieved.

Overexpression of p27BBP in head and neck carcinomas and their lymph node metastases.

Background: p27(BBP) is a regulator of ribosome assembly and an essential nuclear and cytoplasmic component of eukaryotes.

Methods: We investigated the immunochemical distribution of p27(BBP) in head and neck carcinomas, in the associated normal mucosa, and in regional lymph nodes.

Results: p27(BBP) is detectable in mucosal cells but is overexpressed in carcinomas, highly concentrated in large polymorphous nucleoli, and even larger and more evident in lymph node metastatic foci.

Crystal structure of the glutaredoxin-like protein SH3BGRL3 at 1.6 Angstrom resolution.

We report the 1.6 Angstrom resolution crystal structure of SH3BGRL3, a member of a new mammalian protein family of unknown function. The observed "thioredoxin fold" of SH3BGRL3 matches the tertiary structure of glutaredoxins, even in the N-terminal region where the sequence similarity between the two protein families is negligible.