Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability
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 (TEdef), which impairs...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-02-01
|
| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523321003144 |
| _version_ | 1798035651554181120 |
|---|---|
| author | B. Muhammad L.G. Parks K. Komurov L.M. Privette Vinnedge |
| author_facet | B. Muhammad L.G. Parks K. Komurov L.M. Privette Vinnedge |
| author_sort | B. Muhammad |
| collection | DOAJ |
| description | 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 (TEdef), 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 TEdef have widespread overexpression of the components of the protein homeostasis machinery (mostly composed of short genes), including protein folding and clearance. Accordingly, TEdef cells were characterized by abnormally high levels of insoluble protein aggregates in the cytoplasm and autophagy influx. We present evidence that TEdef 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. |
| first_indexed | 2024-04-11T21:00:19Z |
| format | Article |
| id | doaj.art-90bf6d29d0a047e1983a87b524d1dddd |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-04-11T21:00:19Z |
| publishDate | 2022-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-90bf6d29d0a047e1983a87b524d1dddd2022-12-22T04:03:31ZengElsevierTranslational Oncology1936-52332022-02-0116101323Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerabilityB. Muhammad0L.G. Parks1K. Komurov2L.M. Privette Vinnedge3Division 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 StatesDivision of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC7018, 3333 Burnet Avenue, Cincinnati, OH 45229, United StatesDivision 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; Corresponding authors: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.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; Corresponding authors: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.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 (TEdef), 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 TEdef have widespread overexpression of the components of the protein homeostasis machinery (mostly composed of short genes), including protein folding and clearance. Accordingly, TEdef cells were characterized by abnormally high levels of insoluble protein aggregates in the cytoplasm and autophagy influx. We present evidence that TEdef 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.http://www.sciencedirect.com/science/article/pii/S1936523321003144Transcription elongation defects (TEdef)AggresomesProtein homeostasisProteotoxic stressAutophagy |
| spellingShingle | B. Muhammad L.G. Parks K. Komurov L.M. Privette Vinnedge Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability Translational Oncology Transcription elongation defects (TEdef) Aggresomes Protein homeostasis Proteotoxic stress Autophagy |
| title | Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability |
| title_full | Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability |
| title_fullStr | Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability |
| title_full_unstemmed | Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability |
| title_short | Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability |
| title_sort | defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability |
| topic | Transcription elongation defects (TEdef) Aggresomes Protein homeostasis Proteotoxic stress Autophagy |
| url | http://www.sciencedirect.com/science/article/pii/S1936523321003144 |
| work_keys_str_mv | AT bmuhammad defectivetranscriptionelongationinhumancancersimposestargetableproteotoxicvulnerability AT lgparks defectivetranscriptionelongationinhumancancersimposestargetableproteotoxicvulnerability AT kkomurov defectivetranscriptionelongationinhumancancersimposestargetableproteotoxicvulnerability AT lmprivettevinnedge defectivetranscriptionelongationinhumancancersimposestargetableproteotoxicvulnerability |