title: The bad seed gardener: Deubiquitinases in the cancer stem-cell signaling network and therapeutic resistance.
abstract: Tumors are comprised of highly heterogeneous populations of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumors in vivo. These rare cancer stem cells (CSCs) have been regarded as the "bad seeds" accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. CSC-targeted therapy seems to be a better avenue for radical cure of cancer. Deubiquitinases (DUBs), specifically disassembling ubiquitin chains, have been demonstrated to play an important role in rigidly maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis in normal circumstances. Dysfunction or deregulation of DUBs always leads to a series of disorders, even malignant transformation. Despite the accumulative evidence that DUB inhibitors in cancer remedy mainly target the tumor bulk, side effects like toxicity and resistance are still hard nuts to crack. In this article, we review the concept of ubiquitin proteasome system (UPS) and hallmarks of CSCs related to tumor obstinacy. We primarily summarize the CSC-related factors and signaling pathways and focus on the function of DUBs on biological traits of CSCs. We also illustrate the opportunities and challenges for the application of DUB inhibitors in the CSC-targeted therapy. Finally, we discuss the complexity of cancer stem cell hierarchy complexity and argue that a combination therapy for both CSCs and non-CSCs should be a desirable option.
authors.affiliation: Department of Neurosurgery, General Hospital of Jinan Military Command, Jinan 250031, PR China.
authors.forename: Guan-Zhong
authors.initials: GZ
authors.lastname: Qiu
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Ming-Zhu
authors.initials: MZ
authors.lastname: Jin
authors.affiliation: Department of Neurosurgery, General Hospital of Western Air Force, Chengdu 610061, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, General Hospital of Jinan Military Command, Jinan 250031, PR China. Electronic address: pglu912@126.com.
authors.forename: Pei-Gang
authors.initials: PG
authors.lastname: Lu
authors.affiliation: Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China; National Centers for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: weilinjin@yahoo.com.
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Jin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000072017:Deubiquitinating Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D014411:Neoplastic Stem Cells / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000072017:Deubiquitinating Enzymes
keywords: Cancer stem cell; DUB inhibitor; Deubiquitinase; Epithelial-mesenchymal transition; Reprogramming factor; Therapeutic resistance