Genetic Variant of Notch Regulator DTX1 Predicts Survival After Lung Cancer Surgery

Lee, Jang Hyuck; Shin, Kyung Min; Lee, Shin Yup; Hong, Mi Jeong; Choi, Jin Eun; Kang, Hyo Gyoung; Do, Sook Kyung; Lee, Won Kee; Lee, Eung Bae; Seok, Yangki; Jeong, Ji Yun; Yoo, Seung Soo; Lee, Jaehee; Ick, Seung; Kim, Chang Ho; Cho, Sukki; Jheon, Sanghoon; Kim, Young Chul; Oh, In Jae; Na, Kook Joo; Kim, Moon Soo; Lee, Jong Mog; Yang, Hee Chul; Jung, Chi Young; Park, Chang Kwon; Lee, Min Ki; Kim, Dong Kwan; Park, Jae Yong

doi:10.1245/s10434-019-07614-2

Cited by 5 publications

(7 citation statements)

References 28 publications

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“…Genetic variants in the Notch-related genes have been explored in survival analysis of nonsmall lung cancer, cutaneous melanoma and epithelial ovarian cancer 19,20,28,29 but not in CRC, and few studies further explored biological roles of genetic variants of the Notch-related genes in cancer development and progression. The present study was the first that comprehensively evaluated associations between genetic variants in the Notch pathway-related genes and CRC survival and further explored the candidate gene functions with possible mechanisms that explain the observed associations.…”

Section: Discussionmentioning

confidence: 99%

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer

Zhao

Wang

et al. 2021

Intl Journal of Cancer

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Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two‐stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10−6, false discovery rate < 0.01). This locus containing seven single‐nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55‐2.54, P = 6.8 × 10−8). Further analysis of ChIP‐sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis‐regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene‐set enrichment analysis. In vitro, RNAi‐mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings.

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Section: Discussionmentioning

confidence: 99%

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer

Zhao

Wang

et al. 2021

Intl Journal of Cancer

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“…Almost all these mutations occur in the WWE domains of DTX1 and impair its function as a negative Notch regulator, thereby promoting the development of DLBCLs ( Meriranta et al, 2017 ). Mutations in the promoter region of DTX1 were detected during early non-small-cell lung cancer (NSCLC); both overall survival (OS) and disease-free survival (DFS) rates were higher in patients with mutations than in those without mutations, suggesting that DTX1 mutations were beneficial for the survival and prognosis of patients with early NSCLC ( Lee et al, 2019 ). In contrast, patients with small cell lung cancer (SCLC) carrying DTX1 mutations showed a worse response to chemotherapy and a lower OS rate, suggesting that mutations in the same gene may play opposite roles in different subtypes of malignant tumors in the same organ.…”

Section: Functions and Associated Molecular Mechanisms Of The Dtx Familymentioning

confidence: 99%

“…Hepatic cells DTX4 mediates IFN-I signal to influence HBV sustenance and maintenance of HBsAg in chronic hepatitis B (Kim et al, 2018) with mutations than in those without mutations, suggesting that DTX1 mutations were beneficial for the survival and prognosis of patients with early NSCLC (Lee et al, 2019). In contrast, patients with small cell lung cancer (SCLC) carrying DTX1 mutations showed a worse response to chemotherapy and a lower OS rate, suggesting that mutations in the same gene may play opposite (Nafia et al, 2020) roles in different subtypes of malignant tumors in the same organ.…”

Section: Dtx4mentioning

confidence: 99%

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

Wang

Sun

et al. 2021

Front. Cell Dev. Biol.

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Ubiquitination is a posttranslational modification of proteins that significantly affects protein stability and function. The specificity of substrate recognition is determined by ubiquitin E3 ligase during ubiquitination. Human Deltex (DTX) protein family, which functions as ubiquitin E3 ligases, comprises five members, namely, DTX1, DTX2, DTX3, DTX3L, and DTX4. The characteristics and functional diversity of the DTX family proteins have attracted significant attention over the last decade. DTX proteins have several physiological and pathological roles and are closely associated with cell signal transduction, growth, differentiation, and apoptosis, as well as the occurrence and development of various tumors. Although they have been extensively studied in various species, data on structural features, biological functions, and potential mechanisms of action of the DTX family proteins remain limited. In this review, recent research progress on each member of the DTX family is summarized, providing insights into future research directions and potential strategies in disease diagnosis and therapy.

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“…In our previous study, the variant also increased DTX1 mRNA expression in surgically resected NSCLC. 8 Thus, rs1732786A > G could increase DTX1 activity, which would suppress Notch signaling. However, because surgery is rarely used in SCLC, it is difficult to obtain sufficient tissue for examination, so the difference between gene polymorphism and gene expression in SCLC tumor tissue could not be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7] Recently, we reported that genetic variation in the Notch regulator DTX1 can predict the survival of patients with surgically resected NSCLC. 8 In our previous study, DTX1 rs1732786A > G was associated with significantly better overall survival (OS) and diseasefree survival (DFS) rates. Considering that Notch mutations are frequently detected in patients with SCLC, [9][10][11] this variant might also affect SCLC prognosis.…”

Section: Introductionmentioning

confidence: 96%

Effect of genetic variation in Notch regulator DTX1 on SCLC prognosis compared with the effect on NSCLC prongosis

et al. 2020

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Deltex‐1 (DTX1) is a negative regulator of the Notch signaling pathway. Here, we investigated the clinical effect of DTX1 rs1732786A > G, which is associated with better prognosis in patients with early‐stage non‐small cell lung cancer (NSCLC), in 261 patients with small cell lung cancer (SCLC). DTX1 rs1732786A > G was associated with a significantly worse chemotherapy response and lower overall survival in the codominant model (odds ratio = 0.42, 95% confidence interval [CI]: 0.26–0.66, P = 2 × 10−4; hazard ratio = 1.47, 95% CI: 1.17–1.84, P = 0.001, respectively). An in vitro luciferase assay was performed, and the 1732786G allele demonstrated significantly higher promoter activity than the 1732786A allele (P = 2 × 10−7). In summary, DTX1 rs1732786A > G was associated with poor prognosis in patients with SCLC as opposed to patients with NSCLC. Key points Significant findings of the study DTX1 rs1732786A > G was associated with better prognosis in patients with early‐stage non‐small cell lung cancer (NSCLC) in our previous study. What this study adds DTX1 rs1732786A > G was associated with a significantly worse chemotherapy response and lower overall survival in small cell lung cancer (SCLC).

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Genetic Variant of Notch Regulator DTX1 Predicts Survival After Lung Cancer Surgery

Cited by 5 publications

References 28 publications

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

Effect of genetic variation in Notch regulator DTX1 on SCLC prognosis compared with the effect on NSCLC prongosis

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