Involvement of DPP9 in gene fusions in serous ovarian carcinoma

Smebye, Marianne L.; Agostini, Antonio; Johannessen, Bjarne; Thorsen, Jim; Davidson, Ben; Tropé, Claes G.; Heim, Sverre; Skotheim, Rolf Inge; Micci, Francesca

doi:10.1186/s12885-017-3625-6

Cited by 26 publications

(29 citation statements)

References 36 publications

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“…The outcome of this processing and formation of a neo N terminus may alter the life span or activity of a variety of proteins (15,18). They are a focus of attention because of their relevance in immune response and cancer (9,11,(18)(19)(20)46). Therefore, molecular structures of both targets are a valuable basis for development of specific inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer

Ross

Krapp²,

Augustin³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Dipeptidyl peptidases 8 and 9 are intracellular N-terminal dipeptidyl peptidases (preferentially postproline) associated with pathophysiological roles in immune response and cancer biology. While the DPP family member DPP4 is extensively characterized in molecular terms as a validated therapeutic target of type II diabetes, experimental 3D structures and ligand-/substrate-binding modes of DPP8 and DPP9 have not been reported. In this study we describe crystal and molecular structures of human DPP8 (2.5 Å) and DPP9 (3.0 Å) unliganded and complexed with a noncanonical substrate and a small molecule inhibitor, respectively. Similar to DPP4, DPP8 and DPP9 molecules consist of one β-propeller and α/β hydrolase domain, forming a functional homodimer. However, they differ extensively in the ligand binding site structure. In intriguing contrast to DPP4, where liganded and unliganded forms are closely similar, ligand binding to DPP8/9 induces an extensive rearrangement at the active site through a disorder-order transition of a 26-residue loop segment, which partially folds into an α-helix (R-helix), including R160/133, a key residue for substrate binding. As vestiges of this helix are also seen in one of the copies of the unliganded form, conformational selection may contributes to ligand binding. Molecular dynamics simulations support increased flexibility of the R-helix in the unliganded state. Consistently, enzyme kinetics assays reveal a cooperative allosteric mechanism. DPP8 and DPP9 are closely similar and display few opportunities for targeted ligand design. However, extensive differences from DPP4 provide multiple cues for specific inhibitor design and development of the DPP family members as therapeutic targets or antitargets.

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Section: Discussionmentioning

confidence: 99%

“…DPP9 activity is also connected to pathophysiological conditions, as promoting tumoregenicity and metastasis in nonsmall cell lung cancer (19). Recently, DPP9 fusion genes were identified in highgrade serous ovarian carcinoma, suggesting that DPP9 rearrangements might play a role in tumorigenesis or tumor progression (20).…”

mentioning

confidence: 99%

Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer

Ross

Krapp²,

Augustin³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…found CRHR1‐KANSL1 to be the most frequent fusion transcript in their series (2.7% of all tumors). Our group recently reported the involvement of DPP9 in two out of 18 samples of HGSC karyotypically characterized by rearrangements of chromosome 19 8. Taken together, these results suggest that ovarian cancer is not characterized by highly recurrent fusion transcripts.…”

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confidence: 69%

Identification of novel cyclin gene fusion transcripts in endometrioid ovarian carcinomas

Agostini

Brunetti

Davidson

et al. 2018

Intl Journal of Cancer

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Formation of fusion genes is pathogenetically crucial in many solid tumors. They are particularly characteristic of several mesenchymal tumors, but may also be found in epithelial neoplasms. Ovarian carcinomas, too, may harbor fusion genes but only few of these were found to be recurrent with a rate ranging from 0.5 to 5%. Because most attempts to find specific and recurrent fusion transcripts in ovarian carcinomas focused exclusively on high‐grade serous carcinomas, the situation in the other carcinoma subgroups remains largely uninvestigated as far as fusion genes are concerned. We performed transcriptome sequencing on a series of 34 samples from ovarian tumors that included borderline, clear cell, mucinous, endometrioid, low‐grade and high‐grade serous carcinomas in search of fusion genes typical of these subtypes. We found a total of 24 novel fusion transcripts. The PCMTDI‐CCNL2 fusion transcript, which involves a member of the cyclin family, was found recurrently involved but only in endometrioid carcinomas (4 of 18 tumors; 22%). We also found three additional fusion transcripts involving genes belonging to the cyclin family: ANXA5‐CCNA2 and PDE4D‐CCNB1 were detected in two endometrioid carcinomas, whereas CCNY‐NRG4 was identified in a clear cell carcinoma. The recurrent involvement of CCNL2 in four fusions and of three other genes of the cyclin family in three additional transcripts hints that deregulation of cyclin genes is important in the pathogenesis of ovarian carcinomas in general but of endometrioid carcinomas particularly.

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“…Accumulated evidence indicated that WFDC family played great roles in the progression of carcinoma. [28][29][30][31] Additionally, some of them has been identi ed as biomarkers of diagnosis of lung cancer. [32][33][34] Here, the members of WFDC family were selected to do further comprehensive analysis of their roles in lung cancer.…”

Section: Wfdc21p Increases In Lung Carcinoma Cells and Tissuesmentioning

confidence: 99%

miR-4293 Upregulates lncRNA WFDC21P by Directly Suppressing mRNA-Decapping Enzyme 2 to Promote Lung Carcinoma Proliferation

Zhang

Yan

et al. 2020

Preprint

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Background: Emerging evidence shows that lncRNA WFDC21P could promote STAT3 phosphorylation and microRNA 4293 SNP is associated with the risk of carcinomas, but the oncogenic functions of WFDC21P and miR-4293 in lung carcinoma are unclear.Methods: mRNA sequencing of lung carcinoma and control para-carcinoma tissues was performed to screen the potential targets. WFDC21P and miR-4293 levels were evaluated in lung carcinoma cells and tissues by qRT-PCR. The function of WFDC21P and miR-4293 on proliferation, apoptosis and metastasis were assessed by MTT, FACS, western blot, transwell assays, colony formation assays and xenografts experiment. RNA immunoprecipitation assays were implemented to verify the relationship between WFDC21P and mRNA-decapping enzyme 2 (DCP2). Furthermore, gain/loss of miR-4293 functions were used to determine its targeting relationship of DCP2. Results: WFDC21P expression is markedly enhanced in lung carcinoma tissue and cells. Moreover, WFDC21P promotes tumor cell proliferation and metastasis but suppresses apoptosis. Mechanistic investigations identified DCP2 can directly bind to WFDC21P and down-regulates its expression. DCP2 as a direct target of miR-4293 and its expression is suppressed by miR-4293. Consequently, miR-4293 can further promote WFDC21P expression by regulating DCP2. With positive correlation to WFDC21P expression, miR-4293 also plays oncogenic role in lung carcinoma. Furthermore, knockdown of WFDC21P results in functional attenuation of miR-4293 on tumor promotion. In vivo xenograft growth is also promoted by both WFDC21P and miR-4293. Conclusion: Our results establish oncogenic roles for both WFDC21P and miR-4293, and demonstrate that interactions between miRNAs and lncRNAs through DCP2 are important in lung carcinoma pathogenesis.

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Involvement of DPP9 in gene fusions in serous ovarian carcinoma

Cited by 26 publications

References 36 publications

Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer

Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer

Identification of novel cyclin gene fusion transcripts in endometrioid ovarian carcinomas

miR-4293 Upregulates lncRNA WFDC21P by Directly Suppressing mRNA-Decapping Enzyme 2 to Promote Lung Carcinoma Proliferation

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