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Schlafen 5 as a novel therapeutic target in pancreatic ductal adenocarcinoma

Abstract

We provide evidence that a member of the human Schlafen (SLFN) family of proteins, SLFN5, is overexpressed in human pancreatic ductal adenocarcinoma (PDAC). Targeted deletion of SLFN5 results in decreased PDAC cell proliferation and suppresses PDAC tumorigenesis in in vivo PDAC models. Importantly, high expression levels of SLFN5 correlate with worse outcomes in PDAC patients, implicating SLFN5 in the pathophysiology of PDAC that leads to poor outcomes. Our studies establish novel regulatory effects of SLFN5 on cell cycle progression through binding/blocking of the transcriptional repressor E2F7, promoting transcription of key genes that stimulate S phase progression. Together, our studies suggest an essential role for SLFN5 in PDAC and support the potential for developing new therapeutic approaches for the treatment of pancreatic cancer through SLFN5 targeting.

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Fig. 1: SLFN5 is overexpressed in human pancreatic adenocarcinoma tumors.
Fig. 2: Elevated expression of SLFN5 mRNA in pancreatic cancer patient tissues correlates with poor overall survival.
Fig. 3: Loss of SLFN5 reduces pancreatic cancer cell viability in vitro.
Fig. 4: Identification of E2F7 interaction with SLFN5.
Fig. 5: Effects of loss of SLFN5 on cell cycle progression.
Fig. 6: Loss of SLFN5 inhibits tumor growth and prolongs survival in an orthotopic pancreatic cancer xenograft mouse model.
Fig. 7: Proposed model for the role of SLFN5 in pancreatic cancer.

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Acknowledgements

The authors thank Northwestern University’s Pathology Core Facility, the Flow Cytometry Core Facility, and the Proteomics Center of Excellence Core Facility for assistance.

Funding

National Institutes of Health [R01-NS113352, R01-CA77816, R01-CA121192]; Department of Veterans Affairs [I01-CX000916]

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MF, FE, ADA and LCP designed research; MF, FE, GTB, WMM, CVO, REP, CL, EMK, LS and WQ performed research; MF, FE, CL, DS, EMB, DV, GY, WQ, ENF and LCP analyzed data; MF, FE, DS, EMB, ENF and LCP wrote and/or edited the paper; GY, MSL and LCP supervised the study.

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Correspondence to Leonidas C. Platanias.

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Fischietti, M., Eckerdt, F., Blyth, G.T. et al. Schlafen 5 as a novel therapeutic target in pancreatic ductal adenocarcinoma. Oncogene 40, 3273–3286 (2021). https://doi.org/10.1038/s41388-021-01761-1

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