EZH2 Inhibition as New Epigenetic Treatment Option for Pancreatic Neuroendocrine Neoplasms (PanNENs).

April-Monn, Simon Leonhard; Andreasi, Valentina; Schiavo Lena, Marco; Sadowski, Martin Carl; Kim-Fuchs, Corina; Buri, Michelle Claudine; Ketkar, Avanee; Maire, Renaud; Di Domenico, Annunziata; Schrader, Jörg; Muffatti, Francesca; Doglioni, Claudio; Partelli, Stefano; Falconi, Massimo; Perren, Aurel; Marinoni, Ilaria (2021). EZH2 Inhibition as New Epigenetic Treatment Option for Pancreatic Neuroendocrine Neoplasms (PanNENs). Cancers, 13(19) MDPI AG 10.3390/cancers13195014

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Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN preclinical models. EZH2 expression in PanNEN patient samples (n = 172) was assessed by immunohistochemistry and correlated with clinico-pathological data. Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro. Lentiviral transduction of shRNA targeting EZH2 was performed in QGP1 cells, and cell proliferation was measured. Rip1TAG2 mice underwent GSK126 treatment for three weeks starting from week 10 of age. Primary cells isolated from PanNEN patients (n = 6) were cultivated in 3D as islet-like tumoroids and monitored for 10 consecutive days upon GSK126 treatment. Viability was measured continuously for the whole duration of the treatment. We found that high EZH2 expression correlated with higher tumor grade (p < 0.001), presence of distant metastases (p < 0.001), and shorter disease-free survival (p < 0.001) in PanNEN patients. Inhibition of EZH2 in vitro in PanNEN cell lines and in patient-derived islet-like tumoroids reduced cell viability and impaired cell proliferation, while inhibition of EZH2 in vivo in Rip1TAG2 mice reduced tumor burden. Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN.

Item Type:

Journal Article (Original Article)

Division/Institute:

?? 07BEB529942C5BEDE053960C5C82FF48 ??
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

April-Monn, Simon; Andreasi, Valentina; Sadowski, Martin; Kim-Fuchs, Corina; Buri, Michelle Claudine; Ketkar, Avanee; Maire, Renaud Sylvain; Di Domenico, Annunziata; Perren, Aurel and Marinoni, Ilaria

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2072-6694

Publisher:

MDPI AG

Language:

English

Submitter:

Rahel Fuhrer

Date Deposited:

19 Oct 2021 17:27

Last Modified:

06 Dec 2021 11:02

Publisher DOI:

10.3390/cancers13195014

PubMed ID:

34638497

Uncontrolled Keywords:

EZH2 (Enhancer of Zest homolog) epigenetic treatment histone modification pancreatic neuroendocrine neoplasms tumor treatment

BORIS DOI:

10.48350/160176

URI:

https://boris.unibe.ch/id/eprint/160176

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