Proteasomal degradation induced by DPP9‐mediated processing competes with mitochondrial protein import

Finger, Yannik; Habich, Markus; Gerlich, Sarah; Urbanczyk, Sophia; Logt, Erik van de; Koch, Julian; Schu, Laura; Lapacz, Kim Jasmin; Ali, Muna; Petrungaro, Carmelina; Salscheider, Silja Lucia; Pichlo, C.; Baumann, Ulrich; Mielenz, Dirk; Dengjel, Jörn; Brachvogel, Bent; Hofmann, Kay; Riemer, Jan

doi:10.15252/embj.2019103889

Cited by 32 publications

(31 citation statements)

References 94 publications

(141 reference statements)

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“…The top ranking TP53 regulation pathway in our analyses indicates that DPP8 and DPP9 overexpression could be oncogenic in human HCC. The downregulation of metabolism genes with DPP8 and DPP9 upregulation concords with previous data showing that DPP9 deficiency dysregulates metabolic pathways in neonatal liver and gut [ 54 ], and that DPP9 hydrolyses metabolism related substrates including adenylate kinase 2 [ 62 , 63 ] and nucleobindin1 [ 64 ] and regulates preadipocyte differentiation [ 65 ]. Moreover, people with obesity are more likely to develop HCC [ 66 , 67 ].…”

Section: Discussionsupporting

confidence: 85%

DPP9: Comprehensive In Silico Analyses of Loss of Function Gene Variants and Associated Gene Expression Signatures in Human Hepatocellular Carcinoma

Huang

Emran

Endaya

et al. 2021

Cancers

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Dipeptidyl peptidase (DPP) 9, DPP8, DPP4 and fibroblast activation protein (FAP) are the four enzymatically active members of the S9b protease family. Associations of DPP9 with human liver cancer, exonic single nucleotide polymorphisms (SNPs) in DPP9 and loss of function (LoF) variants have not been explored. Human genomic databases, including The Cancer Genome Atlas (TCGA), were interrogated to identify DPP9 LoF variants and associated cancers. Survival and gene signature analyses were performed on hepatocellular carcinoma (HCC) data. We found that DPP9 and DPP8 are intolerant to LoF variants. DPP9 exonic LoF variants were most often associated with uterine carcinoma and lung carcinoma. All four DPP4-like genes were overexpressed in liver tumors and their joint high expression was associated with poor survival in HCC. Increased DPP9 expression was associated with obesity in HCC patients. High expression of genes that positively correlated with overexpression of DPP4, DPP8, and DPP9 were associated with very poor survival in HCC. Enriched pathways analysis of these positively correlated genes featured Toll-like receptor and SUMOylation pathways. This comprehensive data mining suggests that DPP9 is important for survival and that the DPP4 protease family, particularly DPP9, is important in the pathogenesis of human HCC.

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Section: Discussionsupporting

confidence: 85%

DPP9: Comprehensive In Silico Analyses of Loss of Function Gene Variants and Associated Gene Expression Signatures in Human Hepatocellular Carcinoma

Huang

Emran

Endaya

et al. 2021

Cancers

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show abstract

“…The top ranking TP53 regulation pathway in our analyses indicates that DPP8 and DPP9 overexpression could be oncogenic in human HCC. The downregulation of metabolism genes with DPP8 and DPP9 upregulation concords with previous data showing that DPP9 deficiency dysregulates metabolic pathways in neonatal liver and gut [53], and that DPP9 hydrolyses metabolism related substrates including adenylate kinase 2 [59,60] and nucleobindin1 [61] and regulates preadipocyte differentiation [62]. Moreover, people with obesity are more likely to develop HCC [63,64].…”

Section: Discussionsupporting

confidence: 84%

Associations Between DPP9 Expression, Survival and Gene Expression Signature in Human Hepatocellular Carcinoma: Comprehensive In Silico Analyses

Huang¹,

Emran²,

Endaya³

et al. 2021

Preprint

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Dipeptidyl peptidase (DPP) 9, DPP8, DPP4 and fibroblast activation protein (FAP) are the four enzymatically active members of the S9b protease family. Associations of DPP9 with human liver cancer, exonic single nucleotide polymorphisms (SNPs) in DPP9 and loss of function (LoF) variants have not been explored. Human genomic databases including The Cancer Genome Atlas (TCGA) were interrogated to identify DPP9 LoF variants and associated cancers. Survival and gene signature analyses were performed on hepatocellular carcinoma (HCC) data. We found that DPP9 and DPP8 are intolerant to LoF variants. DPP9 LoF variants were most often associated with uterine carcinoma. Two DPP9 intronic SNPs that have been associated with lung fibrosis and COVID-19 were not associated with liver fibrosis or cancer. All four DPP4-like genes were overexpressed in liver tumours and their joint high expression was associated with poor survival in HCC. Increased DPP9 expression was associated with obesity in HCC patients.. High expression of genes that positively correlated with overexpression of DPP4, DPP8, and DPP9 were associated with very poor survival in HCC. Enriched pathways analysis of these positively correlated genes featured Toll-like receptor and SUMOylation pathways. This comprehensive data mining suggests that DPP9 is essential for human survival and the DPP4 protease family is important in cancer pathogenesis.

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“…Several anti-MLS genes in the SHAP analysis were also selected in the linear models, including C6orf89 and DPP9 ( Supplementary Table S6 ). With regards to their functions, it has been shown that C6orf89 exhibits histone deacetylase (HDAC) enhancer properties [ 59 ], while DPP9 regulates mitochondrial protein levels and localization [ 60 ], and is linked to a variety of age-related pathologies including type 2 diabetes, obesity and cancer.…”

Section: Resultsmentioning

confidence: 99%

Machine Learning Analysis of Longevity-Associated Gene Expression Landscapes in Mammals

Kulaga

Ursu

Toren

et al. 2021

IJMS

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One of the important questions in aging research is how differences in transcriptomics are associated with the longevity of various species. Unfortunately, at the level of individual genes, the links between expression in different organs and maximum lifespan (MLS) are yet to be fully understood. Analyses are complicated further by the fact that MLS is highly associated with other confounding factors (metabolic rate, gestation period, body mass, etc.) and that linear models may be limiting. Using gene expression from 41 mammalian species, across five organs, we constructed gene-centric regression models associating gene expression with MLS and other species traits. Additionally, we used SHapley Additive exPlanations and Bayesian networks to investigate the non-linear nature of the interrelations between the genes predicted to be determinants of species MLS. Our results revealed that expression patterns correlate with MLS, some across organs, and others in an organ-specific manner. The combination of methods employed revealed gene signatures formed by only a few genes that are highly predictive towards MLS, which could be used to identify novel longevity regulator candidates in mammals.

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Proteasomal degradation induced by DPP9‐mediated processing competes with mitochondrial protein import

Cited by 32 publications

References 94 publications

DPP9: Comprehensive In Silico Analyses of Loss of Function Gene Variants and Associated Gene Expression Signatures in Human Hepatocellular Carcinoma

DPP9: Comprehensive In Silico Analyses of Loss of Function Gene Variants and Associated Gene Expression Signatures in Human Hepatocellular Carcinoma

Associations Between DPP9 Expression, Survival and Gene Expression Signature in Human Hepatocellular Carcinoma: Comprehensive In Silico Analyses

Machine Learning Analysis of Longevity-Associated Gene Expression Landscapes in Mammals

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