Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells

Abstract

Acinar-to-ductal metaplasia (ADM) occurring in cerulein-mediated pancreatitis or in oncogenic Kras-driven pancreatic cancer development is accompanied by extensive changes in the transcriptional program. In this process, acinar cells shut down the expression of acinar specific differentiation genes and re-express genes usually found in embryonic pancreatic progenitor cells. Previous studies have demonstrated that a loss of acinar-specific transcription factors sensitizes the cells towards oncogenic transformation, ultimately resulting in cancer development. However, the mechanism behind the transcriptional silencing of acinar cell fate genes in ADM and pancreatic cancer is largely unknown. Here, we analyzed whether elevated levels of the polycomb repressor complex 1 (PRC1) components Bmi1 and Ring1b and their catalyzed histone modification H2AK119ub in ADMs and tumor cells, are responsible for the mediation of acinar gene silencing. Therefore, we performed chromatin-immunoprecipitation in in vitro generated ADMs and isolated murine tumor cells against the repressive histone modifications H3K27me3 and H2AK119ub. We established that the acinar transcription factor complex Ptf1-L is epigenetically silenced in ADMs as well as in pancreatic tumor cells. For the first time, this work presents a possible mechanism of acinar gene silencing, which is an important prerequisite in the initiation and maintenance of a dedifferentiated cell state in ADMs and tumor cells.

Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma

“…The chromatin immunoprecipitation assay was performed as previously described. 37 In brief, cells were cross-linked with 1% (vol/vol) formaldehyde in phosphate-buffered saline (PBS) for 10 minutes, lysed in 1% (wt/vol) sodium dodecyl sulfate, and sonicated. Precleared cell lysates were incubated with the antibodies at 4°C overnight.…”

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

“…This interaction can be blocked by inhibitor of β-catenin and TCF4 (ICAT; also known as β-catenin-interacting protein 1) with the net effect of negatively-regulating acinar cell differentiation 26 . Ptf1a has been demonstrated to be epigenetically silenced during inflammation and during oncogenic KRAS-driven ADM in mice 27 . Furthermore, ablation of Ptf1a in mice is sufficient to induce ADM, potentiate inflammation and accelerate development of invasive PDAC by sensitizing cells to KRAS-mediated transformation 28 .…”

Plasticity of differentiated cells in wound repair and tumorigenesis, part I: stomach and pancreas

“…Other transcription factors are keenly involved in acinar cell plasticity ( Fig. 3 B); notably, SOX9 ( Furuyama et al, 2011 ; Prevot et al, 2012 ; Grimont et al, 2015 ), myelocytomatosis oncogene (C-MYC) ( Sanchez-Arevalo Lobo et al, 2017 ) and Kruppel like factor 4 (KLF4) ( Wei et al, 2016 ) promote ADM, whereas PTF1A ( Krah et al, 2015 ; Benitz et al, 2016 ; Hoang et al, 2016 ; Jiang et al, 2016 ; Sanchez-Arevalo Lobo et al, 2017 ), nuclear receptor subfamily 5 group A member 2 (NR5A2) ( Flandez et al, 2014 ; von Figura et al, 2014 ) and BHLH protein E47 ( Kim et al, 2015 ) drive the cells to maintain a more acinar-like differentiated phenotype.…”