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Publication Detail

Title: Deubiquitinase USP7-mediated MCL-1 up-regulation enhances Arsenic and Benzo(a)pyrene co-exposure-induced Cancer Stem Cell-like property and Tumorigenesis.

Authors: Yang, Ping; Xie, Jie; Li, Yunfei; Lin, Hsuan-Pei; Fenske, William; Clementino, Marco; Jiang, Yiguo; Yang, Chengfeng; Wang, Zhishan

Published In Theranostics, (2020)

Abstract: Rationale: MCL-1 is up-regulated in cancer and a target for cancer treatment. How MCL-1 is up-regulated and whether MCL-1 up-regulation plays a role in tumorigenic process is not well-known. Arsenic and benzo(a)pyrene (BaP) are well-recognized lung carcinogens and we recently reported that arsenic and BaP co-exposure acts synergistically in inducing cancer stem cell (CSC)-like property and lung tumorigenesis. This study was performed to further investigate the underlying mechanism focusing on the role of MCL-1. Methods: The spheroid formation assay and nude mouse tumorigenesis assay were used to determine the CSC-like property and tumorigenicity of arsenic plus BaP co-exposure-transformed human bronchial epithelial BEAS-2B cells, respectively. Biochemical, pharmacological and genetic approaches were used to manipulate gene expressions, dissect signaling pathways and determine protein-protein interactions. Both loss-of-function and gain-of-function approaches were used to validate the role of MCL-1 in arsenic plus BaP co-exposure-enhanced CSC-like property and tumorigenicity. Results: Arsenic plus BaP co-exposure-transformed cells express significantly higher protein levels of MCL-1 than the passage-matched control, arsenic or BaP exposure alone-transformed cells. Knocking down MCL-1 levels in arsenic plus BaP co-exposure-transformed cells significantly reduced their apoptosis resistance, CSC-like property and tumorigenicity in mice. Mechanistic studies revealed that arsenic plus BaP co-exposure up-regulates MCL-1 protein levels by synergistically activating the PI3K/Akt/mTOR pathway to increase the level of a deubiquitinase USP7, which in turn reduces the level of MCL-1 protein ubiquitination and prevents its subsequent proteasome degradation. Conclusions: The deubiquitinase USP7-mediated MCL-1 up-regulation enhances arsenic and BaP co-exposure-induced CSC-like property and tumorigenesis, providing the first evidence demonstrating that USP7 stabilizes MCL-1 protein during the tumorigenic process.

PubMed ID: 32802178 Exiting the NIEHS site

MeSH Terms: Animals; Arsenic/adverse effects; Benzo(a)pyrene/adverse effects; Carcinogenesis/chemically induced; Carcinogenesis/genetics*; Cells, Cultured; Deubiquitinating Enzymes/genetics*; Epithelial Cells/drug effects; Female; Humans; Mice; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein/genetics*; Neoplastic Stem Cells/drug effects*; Neoplastic Stem Cells/pathology*; Phosphatidylinositol 3-Kinases/genetics; Proto-Oncogene Proteins c-akt/genetics; Signal Transduction/drug effects; Signal Transduction/genetics; TOR Serine-Threonine Kinases/genetics; Ubiquitin-Specific Peptidase 7/genetics*; Up-Regulation/drug effects; Up-Regulation/genetics*

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