Ubiquitin specific peptidase 37 and PCNA interaction promotes osteosarcoma pathogenesis by modulating replication fork progression.

Autor: Chauhan R; Department of Medical Oncology (Lab), Dr. BRAIRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, Delhi, 110029, India., Gupta A; Department of Medical Oncology (Lab), Dr. BRAIRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, Delhi, 110029, India., Malhotra L; Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India., Bhat AA; Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar., Pandita RK; Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX, USA., Masoodi T; Laboratory of Cancer Immunology and Genetics, Sidra Medicine, Doha, Qatar., Dagar G; Department of Medical Oncology (Lab), Dr. BRAIRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, Delhi, 110029, India., Sadida HQ; Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar., Al-Marzooqi SK; Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar., Batra A; Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India., Bakhshi S; Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India., Sharma MC; Department of Pathology, All India Institute of Medical Sciences, New Delhi, India., Tanwar P; Department of Lab Oncology, Dr. BRAIRCH. All India Institute of Medical Sciences (AIIMS), New Delhi, India., Khan SA; Department of Orthopaedics, Dr. BRAIRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India., Samath EA; Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India., Uddin S; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar., Akil ASA; Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar., Haris M; Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA., Macha MA; Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Pulwama, India., Pandita TK; Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX, USA., Singh M; Department of Medical Oncology (Lab), Dr. BRAIRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, Delhi, 110029, India. mayank.osu@gmail.com.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2023 Apr 28; Vol. 21 (1), pp. 286. Date of Electronic Publication: 2023 Apr 28.
DOI: 10.1186/s12967-023-04126-2
Abstrakt: Background: Osteosarcoma is a type of bone cancer that predominantly affects young individuals, including children and adolescents. The disease progresses through heterogeneous genetic alterations, and patients often develop pulmonary metastases even after the primary tumors have been surgically removed. Ubiquitin-specific peptidases (USPs) regulate several critical cellular processes, such as cell cycle progression, transcriptional activation, and signal transduction. Various studies have revealed the significance of USP37 in the regulation of replication stress and oncogenesis.
Methods: In this study, the Cancer Genome Atlas (TCGA) database was analyzed to investigate USP37 expression. RNA sequencing was utilized to assess the impact of USP37 overexpression and depletion on gene expression in osteosarcoma cells. Various molecular assays, including colony formation, immunofluorescence, immunoprecipitation, and DNA replication restart, were employed to examine the physical interaction between USP37 and PCNA, as well as its physiological effects in osteosarcoma cells. Additionally, molecular docking studies were conducted to gain insight into the nature of the interaction between USP37 and PCNA. Furthermore, immunohistochemistry was performed on archived tissue blocks from osteosarcoma patients to establish a correlation between USP37 and PCNA expression.
Results: Analysis of the TCGA database revealed that increased expression of USP37 was linked to decreased progression-free survival (PFS) in osteosarcoma patients. Next-generation sequencing analysis of osteosarcoma cells demonstrated that overexpression or knockdown of USP37 led to the expression of different sets of genes. USP37 overexpression provided a survival advantage, while its depletion heightened sensitivity to replication stress in osteosarcoma cells. USP37 was found to physically interact with PCNA, and molecular docking studies indicated that the interaction occurs through unique residues. In response to genotoxic stress, cells that overexpressed USP37 resolved DNA damage foci more quickly than control cells or cells in which USP37 was depleted. The expression of USP37 varied in archived osteosarcoma tissues, with intermediate expression seen in 52% of cases in the cohort examined.
Conclusion: The results of this investigation propose that USP37 plays a vital role in promoting replication stress tolerance in osteosarcoma cells. The interaction between USP37 and PCNA is involved in the regulation of replication stress, and disrupting it could potentially trigger synthetic lethality in osteosarcoma. This study has expanded our knowledge of the mechanism through which USP37 regulates replication stress, and its potential as a therapeutic target in osteosarcoma merits additional exploration.
(© 2023. The Author(s).)
Databáze: MEDLINE
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