Genome-wide CRISPR/Cas9 screening identifies CARHSP1 responsible for radiation resistance in glioblastoma

Glioblastomas (GBM) is the most common primary malignant brain tumor, and radiotherapy plays a critical role in its therapeutic management. Unfortunately, the development of radioresistance is universal. Here, we identified calcium-regulated heat-stable protein 1 (CARHSP1) as a critical driver for radioresistance utilizing genome-wide CRISPR activation screening. This is a protein with a cold-shock domain (CSD)-containing that is highly similar to cold-shock proteins. CARHSP1 mRNA level was upregulated in irradiation-resistant GBM cells and knockdown of CARHSP1 sensitized GBM cells to radiotherapy. The high expression of CARHSP1 upon radiation might mediate radioresistance by activating the inflammatory signaling pathway. More importantly, patients with high levels of CARHSP1 had poorer survival when treated with radiotherapy. Collectively, our findings suggested that targeting the CARHSP1/TNF-α inflammatory signaling activation induced by radiotherapy might directly affect radioresistance and present an attractive therapeutic target for GBM, particularly for patients with high levels of CARHSP1.

Cytosolic Distribution of Metals (Cd, Cu) and Metalloids (As, Se) in Livers and Gonads of Field-Collected Fish Exposed to an Environmental Contamination Gradient: An SEC-ICP-MS Analysis

The distribution of As, Cd, Cu and Se among biomolecules of different molecular weight (MW) in the heat-treated cytosolic fraction of livers and gonads of white suckers (WS; Catostomus commersonii) collected in a reference lake and in a lake subject to multi-metal contamination was investigated. Distribution profiles were obtained by separation of the heat-stable protein and peptide (HSP) fractions using size-exclusion high performance-liquid chromatography, coupled online to an inductively coupled plasma mass spectrometer, to quantify the associated metals. Metal-handling strategies did not vary between the reference and exposed fish, with the exception of As. Cadmium and Cu appeared associated with the heat-stable peptides metallothioneins (MTs), indicating their reasonable detoxification and regulation in WS. In contrast, Se and As were not bound to MTs, but rather, to biomolecules of lower MW (<2 kDa). Arsenic was found associated with the same biomolecules in fish from both lakes, but their proportions changed between reference and exposed fish. For future work, the identification of the Se and As binding biomolecules would be of great interest to determine if these metalloids are detoxified or if, conversely, the biomolecules are metal-sensitive and their binding to Se or As represents a threat for the health of these fish.