Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability.

Autor:	Muhammad B; Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC7018, 3333 Burnet Avenue, Cincinnati, OH 45229, United States; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States., Parks LG; Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC7018, 3333 Burnet Avenue, Cincinnati, OH 45229, United States., Komurov K; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. Electronic address: komurov@hotmail.com., Privette Vinnedge LM; Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC7018, 3333 Burnet Avenue, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. Electronic address: Lisa.Privette@cchmc.org.
Jazyk:	angličtina
Zdroj:	Translational oncology [Transl Oncol] 2022 Feb; Vol. 16, pp. 101323. Date of Electronic Publication: 2021 Dec 23.
DOI:	10.1016/j.tranon.2021.101323
Abstrakt:	Successful cancer therapy is contingent on identifying cancer-specific aberrant phenotypes and their associated vulnerabilities. We recently reported that a subset of almost every cancer type contains a genome-wide defect in RNA Polymerase II-mediated transcription elongation (TE def ), which impairs the expression of long genes and confers resistance to anti-tumor immune attack. Using a combination of computational analysis and laboratory experiments, we report that tumor cells with TE def have widespread overexpression of the components of the protein homeostasis machinery (mostly composed of short genes), including protein folding and clearance. Accordingly, TE def cells were characterized by abnormally high levels of insoluble protein aggregates in the cytoplasm and autophagy influx. We present evidence that TE def cells exhibit impaired clearance of misfolded protein aggregates through the ubiquitin-proteasome system, and thus rely on autophagy for their degradation. As such, while these cells were highly resistant to proteasome inhibitors, they were acutely sensitive to inhibitors of autophagy in vitro and in vivo. This study reveals a major aberrant phenotype that is observed in ∼15-25% of all cancers and characterizes a unique cellular vulnerability that can be readily exploited in the clinic to improve treatment efficacy. (Copyright © 2021. Published by Elsevier Inc.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu