USP14 Regulates DNA Damage Response and Is a Target for Radiosensitization in Non-Small Cell Lung Cancer

Sharma, Arishya; Almasan, Alexandru

doi:10.3390/ijms21176383

Cited by 24 publications

(18 citation statements)

References 49 publications

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“…et al, 2019 ; Xu et al, 2020 ). The IC 50 of IU1 is 4.7 μM 5 , and concentrations of 50–100 μM IU1 have been used in multiple cancer cells ( Li H. et al, 2019 ; Xia et al, 2019 ; Sharma et al, 2020 ; Sharma and Almasan, 2020 ). We found that the viability of AGS and MKN-28 cells was remarkably suppressed by 75–100 μM IU1, while not in BGC-823 cells ( Figure 6J ).…”

Section: Resultsmentioning

confidence: 99%

The m6A Reader YTHDF1 Facilitates the Tumorigenesis and Metastasis of Gastric Cancer via USP14 Translation in an m6A-Dependent Manner

Chen

Liang

et al. 2021

Front. Cell Dev. Biol.

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ObjectivesN6-methyladenosine (m6A) RNA methylation is implicated in the progression of multiple cancers via influencing mRNA modification. YTHDF1 can act as an oncogene in gastric cancer (GC), while the biological mechanisms via which YTHDF1 regulates gastric tumorigenesis through m6A modification remain largely unknown.MethodsGEO and TCGA cohorts were analyzed for differentially expressed m6A modification components in GC clinical specimens and their association with clinical prognosis. Transwell and flow cytometry assays as well as subcutaneous xenograft and lung metastasis models were used to evaluate the phenotype of YTHDF1 in GC. Intersection of RNA/MeRIP-seq, luciferase assay, RIP-PCR, RNA pull-down and MeRIP-PCR was used to identify YTHDF1- modified USP14 and its m6A levels in GC cells.ResultsHigh-expressed YTHDF1 was found in GC tissues and was related to poor prognosis, acting as an independent prognostic factor of poor survival in GC patients. YTHDF1 deficiency inhibited cell proliferation and invasion (in vitro), and gastric tumorigenesis and lung metastasis (in vivo) and also induced cell apoptosis. Intersection assays revealed that YTHDF1 promoted USP14 protein translation in an m6A-dependent manner. USP14 upregulation was positively correlated with YTHDF1 expression and indicated a poor prognosis in GC.ConclusionOur data suggested that m6A reader YTHDF1 facilitated tumorigenesis and metastasis of GC by promoting USP14 protein translation in an m6A-dependent manner and might provide a potential target for GC treatment.

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Section: Resultsmentioning

confidence: 99%

The m6A Reader YTHDF1 Facilitates the Tumorigenesis and Metastasis of Gastric Cancer via USP14 Translation in an m6A-Dependent Manner

Chen

Liang

et al. 2021

Front. Cell Dev. Biol.

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“…In vitro and in vivo studies have shown that genetic and pharmacological inhibition of USP14 induces degradation of an androgen receptor (AR), favoring tumor suppression in AR-positive breast cancer cells or prostate cancer cells ( Liao et al, 2017 ; Liao et al, 2018 ). USP14 promotes tumor growth by regulating DNA damage response or ER stress-mediated autophagy in non-small cell lung cancer cells ( Moghadami et al, 2020 ; Sharma and Almasan, 2020 ). Alone this line, several compounds targeting UCHL5 and USP14 have been developed, including b-AP15 ( D'Arcy et al, 2011 ), VLX1570 (b-AP15 analog) ( Wang et al, 2016 ), AC17 (curcumin analog) ( Zhou et al, 2013 ), and various metal-based complexes ( Liu et al, 2014b ; Chen et al, 2018a ; Li et al, 2019a ).…”

Section: Targeting Dubs: a Novel Strategy For Cancer Therapymentioning

confidence: 99%

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

Chen

Dou

Liu

et al. 2021

Front. Mol. Biosci.

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Characterizing mechanisms of protein homeostasis, a process of balancing between protein synthesis and protein degradation, is important for understanding the potential causes of human diseases. The ubiquitin–proteasome system (UPS) is a well-studied mechanism of protein catabolism, which is responsible for eliminating misfolded, damaged, or aging proteins, thereby maintaining quality and quantity of cellular proteins. The UPS is composed of multiple components, including a series of enzymes (E1, E2, E3, and deubiquitinase [DUB]) and 26S proteasome (19S regulatory particles + 20S core particle). An impaired UPS pathway is involved in multiple diseases, including cancer. Several proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, are approved to treat patients with certain cancers. However, their applications are limited by side effects, drug resistance, and drug–drug interactions observed in their clinical processes. To overcome these shortcomings, alternative UPS inhibitors have been searched for in many fields. Copper complexes (e.g., CuET, CuHQ, CuCQ, CuPDTC, CuPT, and CuHK) are found to be able to inhibit a core component of the UPS machinery, such as 20S proteasome, 19S DUBs, and NPLOC4/NPL4 complex, and are proposed to be one class of metal-based anticancer drugs. In this review, we will summarize functions and applications of copper complexes in a concise perspective, with a focus on connections between the UPS and cancer.

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“…DNA damage is one of the major causes of radioresistance in lung cancer [ 153 ]. Ubiquitin-specific protease 14 (USP14) acts as a regulator [ 154 ] in double strand breaks (DSBs), which affects both non-homologous end-joining (NHEJ) and HR [ 155 , 156 ]. Knocking down USP14 by using short hairpin RNA (shRNA) showed a notable increase in the radiosensitivity of NSCLCs [ 154 ].…”

Section: Mechanism Of Radiotherapy Resistance In Lung Cancermentioning

confidence: 99%

Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

Ashrafi

Akter

Modareszadeh

et al. 2022

Cancers

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Lung cancer is one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 18%. Current treatment modalities include surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Despite advances in therapeutic options, resistance to therapy remains a major obstacle to the effectiveness of long-term treatment, eventually leading to therapeutic insensitivity, poor progression-free survival, and disease relapse. Resistance mechanisms stem from genetic mutations and/or epigenetic changes, unregulated drug efflux, tumor hypoxia, alterations in the tumor microenvironment, and several other cellular and molecular alterations. A better understanding of these mechanisms is crucial for targeting factors involved in therapeutic resistance, establishing novel antitumor targets, and developing therapeutic strategies to resensitize cancer cells towards treatment. In this review, we summarize diverse mechanisms driving resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and promising strategies to help overcome this therapeutic resistance.

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USP14 Regulates DNA Damage Response and Is a Target for Radiosensitization in Non-Small Cell Lung Cancer

Cited by 24 publications

References 49 publications

The m6A Reader YTHDF1 Facilitates the Tumorigenesis and Metastasis of Gastric Cancer via USP14 Translation in an m6A-Dependent Manner

The m6A Reader YTHDF1 Facilitates the Tumorigenesis and Metastasis of Gastric Cancer via USP14 Translation in an m6A-Dependent Manner

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

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