Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity

Kim, Dong Gyun; Cho, Su Jin; Lee, Kyu Yeon; Cheon, Seung Ho; Yoon, Hye Jin; Lee, Joo Youn; Kim, Dong-Yoon; Shin, Kyung-Hoon; Koh, Choong Hyun; Koo, Ji Sung; Choi, Yuri; Lee, Hyung Ho; Oh, Yu‐Kyoung; Jeong, Yonghwan; Chung, Suk Jae; Baek, Moonkyu; Jung, Kwan Young; Lim, Hyo Jin; Kim, Hyoun Sook; Park, Sung Jean; Lee, Jeong Yeon; Lee, Sang Jae; Lee, Bong Jin

doi:10.1007/s00018-020-03490-2

Cited by 10 publications

(4 citation statements)

References 48 publications

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“…Dysregulation or imbalance of cholesterol metabolic pathways contributes to many human diseases such as atherosclerosis, neuropathy, and cancer progression 12,13 . Several recent studies have demonstrated that dysregulated cholesterol metabolism is a salient feature in the progression of cancer 14,15 . In the present study, we found that NSDHL and NCEH1 were significantly overexpressed in patients with gastric cancer.…”

Section: Discussionsupporting

confidence: 62%

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NAD(P)‐dependent steroid dehydrogenase‐like protein and neutral cholesterol ester hydrolase 1 serve as novel markers for early detection of gastric cancer identified using quantitative proteomics

Xiao

Xie

Liu

et al. 2020

Clinical Laboratory Analysis

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Background Gastric cancer (GC) is the third most common cause of cancer deaths worldwide. In the present study, we aimed to identify novel GC biomarkers by integrating isobaric tags of relative and absolute quantitation (iTRAQ) for aberrantly expressed proteins in GC patients. Methods Using stable isotope tags, we labeled an initial discovery group comprising four paired gastric cancer and adjacent gastric tissue samples, and subjected them to LC‐ESI‐MS/MS. We used a validation set comprising 129 paired gastric cancer and adjacent gastric tissues from patients and benign healthy controls to validate the candidate targets. Results We identified two proteins, NAD(P)‐dependent steroid dehydrogenase‐like (NSDHL) and neutral cholesterol ester hydrolase 1 (NCEH1), that were significantly overexpressed in GC tissues. The sensitivity and specificity of NSDHL were 80.6% and 74.4%, respectively, in GC compared with a sensitivity of 25.6% in adjacent tissues and 24% in benign healthy controls. The area under the ROC curve (AUC) for NSDHL was 0.810 for GC detection. Overexpression of NSDHL in GC was significantly correlated with local tumor invasion. The sensitivity and specificity of NCEH1 were 77.5% and 73.6%, respectively, in GC compared with a sensitivity of 26.4% in adjacent tissues and 20% in benign controls. The AUC for NSDHL was 0.792. Overexpression of NCEH1 was significantly associated with tumor histological classification and local invasion. Moreover, a combined analysis of NSDHL and NCEH1 achieved a sensitivity and specificity of 85.7% and 83%, respectively, and the AUC was 0.872. The combined analysis of NSDHL and NCEH1 was significantly correlated with histological grade and TNM Ⅱ‐Ⅳ staging. Conclusions iTRAQ‐labeled quantitative proteomics represents a powerful method to identify novel cancer biomarkers. The present study identified NSDHL and NCEH1 as useful biomarkers for screening, diagnosis, and prognosis of patients with gastric cancer.

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Section: Discussionsupporting

confidence: 62%

“…The results revealed that compound 9 decreased EGFR expression and signal transduction. Moreover, when combined with an EGFR inhibitor, compound 9 enhanced its antitumor effect 14 …”

Section: Discussionmentioning

confidence: 99%

NAD(P)‐dependent steroid dehydrogenase‐like protein and neutral cholesterol ester hydrolase 1 serve as novel markers for early detection of gastric cancer identified using quantitative proteomics

Xiao

Xie

Liu

et al. 2020

Clinical Laboratory Analysis

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“…There is a dual localization of this protein, within the membranes of endoplasmic reticulum and on the surface of lipid droplets. Dysregulation of this pathway has also shown to cause metabolic derangements such as hypercholesterolemia, certain cancers, cardiovascular diseases and neuropathies [5][6][7]. Here we report the first Sri Lankan patient with CHILD syndrome due to a novel heterozygous variant (NSDHL, c.713C > A, p.Thr238Asn).…”

Section: Introductionmentioning

confidence: 89%

Novel variant in NSDHL gene associated with CHILD syndrome and syndactyly- a case report

et al. 2020

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Background: Congenital hemidysplasia with ichthyosiform erythroderma and limb defects also known as CHILD syndrome is an X-linked dominant, male lethal genodermatosis with a prevalence of 1 in 100,000 live births. Mutations in NSDHL gene located at Xq28 potentially impair the function of NAD(P) H steroid dehydrogenase-like protein and is responsible for its pathogenesis. Case presentation: The proband was a 9-month-old twin (T2) girl with a healthy twin sister (T1) of Sri Lankan origin born to non-consanguineous parents. She presented with right sided continuous icthyosiform erythroderma and ipsilateral limb defects and congenital hemidysplasia since birth. Notably the child had ipsilateral hand hypoplasia and syndactyly. There were other visceral abnormalities. We performed whole exome sequencing and found a novel heterozygous variant (NSDHL, c.713C > A, p.Thr238Asn). Conclusion: We report a novel missense variant in the NSDHL gene that resides in a highly-conserved region. This variant affects the NAD(P) H steroid dehydrogenase-like protein function via reduction in the number of active sites resulting in the CHILD syndrome phenotype and syndactyly.

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“…AR mutations in the kinase domain increase PTEN expression [ 46 , 47 , 48 , 49 ]. Increased PTEN expression regulates the expression of protein killin (KLLN) and promotes p53 and p73 expression, subsequently augmenting apoptosis [ 50 , 51 ]. GATA-3, an important transcription factor, is involved in luminal cell differentiation and restricts the effects of drugs by enhancing ER signaling activity [ 49 ].…”

Section: Targets Of Tnbc Under Active Clinical Evaluationmentioning

confidence: 99%

TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy

Singh

Yadav

2021

Biomedicines

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Triple-negative breast cancer (TNBC) is a heterogeneous, recurring cancer associated with a high rate of metastasis, poor prognosis, and lack of therapeutic targets. Although target-based therapeutic options are approved for other cancers, only limited therapeutic options are available for TNBC. Cell signaling and receptor-specific targets are reportedly effective in patients with TNBC under specific clinical conditions. However, most of these cancers are unresponsive, and there is a requirement for more effective treatment modalities. Further, there is a lack of effective biomarkers that can distinguish TNBC from other BC subtypes. ER, PR, and HER2 help identify TNBC and are widely used to identify patients who are most likely to respond to diverse therapeutic strategies. In this review, we discuss the possible treatment options for TNBC based on its inherent subtype receptors and pathways, such as p53 signaling, AKT signaling, cell cycle regulation, DNA damage, and programmed cell death, which play essential roles at multiple stages of TNBC development. We focus on poly-ADP ribose polymerase 1, androgen receptor, vascular endothelial growth factor receptor, and epidermal growth factor receptor as well as the application of nanomedicine and immunotherapy in TNBC and discuss their potential applications in drug development for TNBC.

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Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity

Cited by 10 publications

References 48 publications

NAD(P)‐dependent steroid dehydrogenase‐like protein and neutral cholesterol ester hydrolase 1 serve as novel markers for early detection of gastric cancer identified using quantitative proteomics

NAD(P)‐dependent steroid dehydrogenase‐like protein and neutral cholesterol ester hydrolase 1 serve as novel markers for early detection of gastric cancer identified using quantitative proteomics

Novel variant in NSDHL gene associated with CHILD syndrome and syndactyly- a case report

TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy

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