NEDD4: A Promising Target for Cancer Therapy

Ye, Xiantao; Wang, Lixia; Shang, Bingxue; Wang, Zhiwei; Wei, Wenyi

doi:10.2174/1568009614666140725092430

Cited by 65 publications

(50 citation statements)

References 51 publications

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“…Among these UPS members, the E3 ubiquitin ligase possesses a high variability of their components and interacts directly with ubiquitin substrates and determines the substrate specificity [17]. Neuronally expressed developmentally downregulated 4 (NEDD4, often known as NEDD4-1), a homologue to E6-AP C-terminus (HECT) family of E3 ubiquitin ligase, plays a critical role in the development and progression of many human cancers [18][19][20][21]. Amodio et al demonstrated that NEDD4 facilitated non-smallcell lung carcinomas (NSCLC) cell lines proliferation through inactivation of PTEN [22].…”

Section: Introductionsmentioning

confidence: 99%

NEDD4 promotes cell growth and motility in hepatocellular carcinoma

Zheng

et al. 2018

Cell Cycle

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Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. In China, the situation is even worse as cancer incidence and mortality continue to increase rapidly. Although tremendous progress has been made toward HCC treatments, the benefits for liver cancer patients are still limited. Therefore, it is necessary to identify and develop novel therapeutic methods. Neuronally expressed developmentally downregulated 4 (NEDD4), an E3 ubiquitin ligase, plays a critical role in the development and progression of various types of human cancers. In our study, NEDD4 acts as an oncoprotein in both QGY7703 and SMMC7721 liver cancer cell lines. We found that depletion of NEDD4 by siRNA transfection led to inhibition of cell growth, invasion and migration, and promotion of apoptosis. In contrast, overexpression of NEDD4 via plasmid transfection resulted in facilitated cell proliferation, invasion and migration, and decreased apoptosis. Importantly, we observed that tumor suppressor LATS1, also a core component of Hippo pathway, was negatively regulated by NEDD4 in liver cancer cells. Our findings suggested that NEDD4 may be involved in the HCC progression via regulating LATS1 associated signaling pathway. Therefore, targeting NEDD4-LATS1 signaling could be a potential therapeutic option for HCC treatment.

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Section: Introductionsmentioning

confidence: 99%

NEDD4 promotes cell growth and motility in hepatocellular carcinoma

Zheng

et al. 2018

Cell Cycle

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“…However, increasing evidence suggests that NEDD4 may also promote cancer cell growth independently of PTEN (Eide et al, 2013;Zou et al, 2015). NEDD4 is a potential target protein in cancer therapy, and obtaining a clearer understanding of the role of NEDD4 in cancer pathogenesis may therefore have future clinical implications (Ye et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

The E3 ubiquitin ligase NEDD4 induces endocytosis and lysosomal sorting of connexin 43 to promote loss of gap junctions

Totland

Bergsland

Fykerud

et al. 2017

Journal of Cell Science

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Intercellular communication via gap junctions has an important role in controlling cell growth and in maintaining tissue homeostasis. Connexin 43 (Cx43; also known as GJA1) is the most abundantly expressed gap junction channel protein in humans and acts as a tumor suppressor in multiple tissue types. Cx43 is often dysregulated at the post-translational level during cancer development, resulting in loss of gap junctions. However, the molecular basis underlying the aberrant regulation of Cx43 in cancer cells has remained elusive. Here, we demonstrate that the oncogenic E3 ubiquitin ligase NEDD4 regulates the Cx43 protein level in HeLa cells, both under basal conditions and in response to protein kinase C activation. Furthermore, overexpression of NEDD4, but not a catalytically inactive form of NEDD4, was found to result in nearly complete loss of gap junctions and increased lysosomal degradation of Cx43 in both HeLa and C33A cervical carcinoma cells. Collectively, the data provide new insights into the molecular basis underlying the regulation of gap junction size and represent the first evidence that an oncogenic E3 ubiquitin ligase promotes loss of gap junctions and Cx43 degradation in human carcinoma cells.

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“…NEDD4L is an ubiquitin ligase of the NEDD4 family and is the closest homologue to NEDD4, which play a critical regulatory role in the development and progression of many human cancers (Ye et al 2014). NEDD4L is a regulator of the WNT pathway Zhang et al 2014), and its expression is down-regulated in ovarian and colorectal cancers (Tanksley et al 2013;Yang et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

Zhou

Greer

Spies

et al. 2018

Preprint

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HepG2 is one of the most widely used human cell lines in biomedical research and one of the main cell lines of ENCODE. Although the functional genomic and epigenomic characteristics of HepG2 are extensively studied, its genome sequence has never been comprehensively analyzed and higher-order structural features of its genome beyond its karyotype were only cursorily known. The high degree of aneuploidy in HepG2 renders traditional genome variant analysis methods challenging and partially ineffective. Correct and complete interpretation of the extensive functional genomics data fromHepG2 requires an understanding of the cell line's genome sequence and genome structure. We performed deep whole-genome sequencing, mate-pair sequencing and linked-read sequencing to identify a wide spectrum of genome characteristics in HepG2: copy numbers of chromosomal segments, SNVs and Indels (both corrected for copynumber), phased haplotype blocks, structural variants (SVs) including complex genomic rearrangements, and novel mobile element insertions. A large number of SVs were phased, sequence assembled and experimentally validated. Several chromosomes show striking loss of heterozygosity. We re-analyzed HepG2 RNA-Seq and wholegenome bisulfite sequencing data for allele-specific expression and phased DNA methylation. We show examples where deeper insights into genomic regulatory complexity could be gained by taking knowledge of genomic structural contexts into account. Furthermore, we used the haplotype information to produce an allele-specific CRISPR targeting map. This comprehensive whole-genome analysis serves as a resource for future studies that utilize HepG2.

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NEDD4: A Promising Target for Cancer Therapy

Cited by 65 publications

References 51 publications

NEDD4 promotes cell growth and motility in hepatocellular carcinoma

NEDD4 promotes cell growth and motility in hepatocellular carcinoma

The E3 ubiquitin ligase NEDD4 induces endocytosis and lysosomal sorting of connexin 43 to promote loss of gap junctions

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

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