CUL4A expression is associated with tumor stage and prognosis in nasopharyngeal carcinoma

Jin, Xin; Ma, Yong-Chi; Zhu, Weiwei; Fan, Lun

doi:10.1097/md.0000000000018036

Cited by 5 publications

(4 citation statements)

References 37 publications

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“…CUL4A has similar oncogenic effects in nasopharyngeal carcinoma. The expression of CUL4A has been directly related to cancer stage and prognosis in nasopharyngeal carcinoma [26]. Meanwhile, we found that an increased transcriptional level of CUL4A was shown in HNSCC samples, and the level of CUL4A mRNA could be correlated to clinic-pathological features.…”

Section: Discussionmentioning

confidence: 76%

Bioinformatics analysis of CUL2/4A/9 and its function in head and neck squamous cell carcinoma

Wang

Zhang

et al. 2023

Endokrynol Pol

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Section: Discussionmentioning

confidence: 76%

Bioinformatics analysis of CUL2/4A/9 and its function in head and neck squamous cell carcinoma

Wang

Zhang

et al. 2023

Endokrynol Pol

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“…Conversely, overexpression of CUL4A reduced cisplatin efficacy in HNSCC models. Since CUL4A has been previously reported to be overexpressed in nasopharyngeal and esophageal squamous cell carcinoma, this provides further rationale for the investigation of pevonedistat for HNSCC therapy [ 42 , 43 ]. Surprisingly, the augmentation of cisplatin-induced DNA damage and apoptosis by pevonedistat or CUL4A knockdown was shown to be mediated through the downregulation of DDB2, which is required for NER.…”

Section: Discussionmentioning

confidence: 99%

Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism

et al. 2022

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Patients with late-stage and human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) continue to have a very poor prognosis. The development of more effective novel therapies that improve overall survival and overcome drug resistance is an urgent priority. Here we report that HNSCC tumors significantly overexpress NEDD8 and exhibit high sensitivity to the first-in-class NEDD8-activating enzyme (NAE) inhibitor pevonedistat. Additional studies established that disruption of NEDD8-mediated protein turnover with pevonedistat dramatically augmented cisplatin-induced DNA damage and apoptosis in HNSCC models. Further analysis revealed that the specific pevonedistat target CUL4A played an essential role in driving the synergy of the pevonedistat and cisplatin combination. Targeted inhibition of CUL4A resulted in significant downregulation in Damage Specific DNA binding protein 2 (DDB2), a DNA-damage recognition protein that promotes nucleotide excision repair and resistance to cisplatin. Silencing of CUL4A or DDB2 enhanced cisplatin-induced DNA damage and apoptosis in a manner similar to that of pevonedistat demonstrating that targeted inhibition of CUL4A may be a novel approach to augment cisplatin therapy. Administration of pevonedistat to mice bearing HNSCC tumors significantly decreased DDB2 expression in tumor cells, increased DNA damage and potently enhanced the activity of cisplatin to yield tumor regression and long-term survival of all animals. Our findings provide strong rationale for clinical investigation of CUL4A inhibition with pevonedistat as a novel strategy to augment the efficacy of cisplatin therapy for patients with HNSCC and identify loss of DDB2 as a key pharmacodynamic mediator controlling sensitivity to this regimen.

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“…Subsequent studies found that CUL4A overexpression also occurred in the prostate, colon, liver, as well as lung cancer [ 12–15 ]. Of note, it was evidenced that CUL4A was overexpressed in NPC [ 16 ], nonetheless, the role of CUL4A, as well as its mechanism, has not been revealed.…”

Section: Introductionmentioning

confidence: 99%

Cullin 4A/protein arginine methyltransferase 5 (CUL4A/PRMT5) promotes cell malignant phenotypes and tumor growth in nasopharyngeal carcinoma

2022

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Targeted therapy is an important therapeutic strategy currently, however, the development of targeted therapy for nasopharyngeal carcinoma (NPC) is relatively lagging. Cullin 4A (CUL4A) was reported to be overexpressed in NPC; nevertheless, the specific role of CUL4A remains unrevealed. NPC cells and tumor-bearing mice were cultivated to explore the role and mechanism of CUL4A in NPC. After evaluating CUL4A levels in NPC cells, functional experiments were carried out to investigate the effects of CUL4A knockdown and overexpression on cell proliferative, invasive and migratory aptitude as well as NF-κB signaling. Following the GeneMANIA database predicted that protein arginine methyltransferase 5 (PRMT5) was downstream of CUL4A, the mediated role of PRMT5 in the regulation of CUL4A on cells was then determined. Moreover, the tumor volumes and weights of tumor-bearing mice were recorded, and the levels of proliferation-, migration-, and NF-κB signaling-related proteins in the tumor were determined. Herein, CUL4A was enhanced in NPC cells, and its knockdown and overexpression separately suppressed and promoted cell proliferative, invasive, and migratory aptitude as well as NF-κB signal activation. Novelty, PRMT5 knockdown reversed the influences of CUL4A overexpression on these aspects. In addition, its knockdown likewise reversed the facilitating impact of CUL4A expression on tumor growth and declined the expression levels of proliferation-, migration-, and NF-κB signaling-related protein in the tumor. Together, this paper indicated that CUL4A promoted the proliferative, invasive, and migratory aptitude of NPC cells as well as tumor growth by promoting PRMT5 to activate NF-κB signaling.

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CUL4A expression is associated with tumor stage and prognosis in nasopharyngeal carcinoma

Cited by 5 publications

References 37 publications

Bioinformatics analysis of CUL2/4A/9 and its function in head and neck squamous cell carcinoma

Bioinformatics analysis of CUL2/4A/9 and its function in head and neck squamous cell carcinoma

Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism

Cullin 4A/protein arginine methyltransferase 5 (CUL4A/PRMT5) promotes cell malignant phenotypes and tumor growth in nasopharyngeal carcinoma

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