bioRxiv preprint doi: https://doi.org/10.1101/2020.01.06.896555; this version posted January 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Regulation of HDAC2-PDX1 by RNF125 defines pancreatic cancer development Erez Hasnis1, Hyungsoo Kim1, Sachin Verma1, Yongmei Feng1, Ronit Almog2, Sivan Matsliah2, Vera Vavinskaya3, Ron Apelbaum2, Offir Ben-Ishay2, David Tuveson4, Rosalie Sears5, Ze’ev A. Ronai1 1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; 2Rambam Health Care Campus, Haifa, Israel; 3Department of Pathology, University of California San Diego, La Jolla, CA, USA; 4Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 5Oregon Health and Science University, Portland, OR Keywords: RNF125, pancreatic cancer, PDA, PDX1, NR5A2, HDAC2, acinar, ductal, ADM Correspondence – Ze’ev A Ronai,
[email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.06.896555; this version posted January 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract There is an urgent need to define mechanisms underlying pancreatic adenocarcinoma (PDA) development. Our studies of ubiquitin ligases that may underlie PDA development led us to identify and characterize RNF125. We show that RNF125 exhibits nuclear expression in acinar cells, with reduced and largely cytosolic expression in ductal cells, PanIN and PDA specimens. We find that RNF125 interacts with histone deacetylase 2 (HDAC2) and promotes its non- canonical K63-linked ubiquitination. Inhibition of HDAC2 activity by RNF125 resulted in elevated expression of the pancreatic and duodenal homeobox 1 (PDX1).