Intrinsically Disordered Regions Define Unique Protein Interaction Networks in CHD Family Remodelers.

Chromodomain helicase DNA-binding (CHD) enzymes play a pivotal role in genome regulation. They possess highly conserved ATPase domains flanked by poorly characterized and intrinsically disordered N- and C-termini. Using mass spectrometry, we identify dozens of novel protein-protein interactions (PPIs) within the N- and C-termini of human CHD family members.

Mesothelin antigen density influences anti-mesothelin chimeric antigen receptor T cell cytotoxicity.

Background Aims: Several anti-mesothelin (MSLN) chimeric antigen receptor (CAR) T cells are in phase 1/2 clinical trials to treat solid-organ malignancies. The effect of MSLN antigen density on MSLN CAR cytotoxicity against tumor cells has not been examined previously, nor are there data regarding the effect of agents that increase MSLN antigen density on anti-MSLN CAR T cell efficacy.

Methods: MSLN antigen density was measured on a panel of pancreatic cancer and mesothelioma cell lines by flow cytometry.

The Fusion of and Arises from a -Splicing Event in Normal and Transformed Human Cells.

Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs.

Structure-function relationships explain CTCF zinc finger mutation phenotypes in cancer.

CCCTC-binding factor (CTCF) plays fundamental roles in transcriptional regulation and chromatin architecture maintenance. CTCF is also a tumour suppressor frequently mutated in cancer, however, the structural and functional impact of mutations have not been examined. We performed molecular and structural characterisation of five cancer-specific CTCF missense zinc finger (ZF) mutations occurring within key intra- and inter-ZF residues.

Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients.

Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken.

CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer.

CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in , which we have shown functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of haploinsufficiency.

The antiproliferative ELF2 isoform, ELF2B, induces apoptosis in vitro and perturbs early lymphocytic development in vivo.

Background: ELF2 (E74-like factor 2) also known as NERF (new Ets-related factor), a member of the Ets family of transcription factors, regulates genes important in B and T cell development, cell cycle progression, and angiogenesis. Conserved ELF2 isoforms, ELF2A, and ELF2B, arising from alternative promoter usage can exert opposing effects on target gene expression. ELF2A activates, whilst ELF2B represses, gene expression, and the balance of expression between these isoforms may be important in maintaining normal cellular function.

Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development.

Glutamine is conditionally essential in cancer cells, being utilized as a carbon and nitrogen source for macromolecule production, as well as for anaplerotic reactions fuelling the tricarboxylic acid (TCA) cycle. In this study, we demonstrated that the glutamine transporter ASCT2 (SLC1A5) is highly expressed in prostate cancer patient samples. Using LNCaP and PC-3 prostate cancer cell lines, we showed that chemical or shRNA-mediated inhibition of ASCT2 function in vitro decreases glutamine uptake, cell cycle progression through E2F transcription factors, mTORC1 pathway activation and cell growth.

Targeting amino acid transport in metastatic castration-resistant prostate cancer: effects on cell cycle, cell growth, and tumor development.

Background: L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth.

Methods: We examined LAT3 protein expression in human prostate cancer tissue microarrays.

The cancer-testis antigen BORIS phenocopies the tumor suppressor CTCF in normal and neoplastic cells.

BORIS and CTCF are paralogous, multivalent 11-zinc finger transcription factors that play important roles in organizing higher-order chromatin architecture. BORIS is a cancer-testis antigen with a poorly defined function in cancer, although it has been hypothesized to exhibit oncogenic properties. CTCF, however, has been postulated as a candidate tumor suppressor.