EZH2 couples pancreatic regeneration to neoplastic progression

Abstract

Although the polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) is well recognized for its role as a key regulator of cell differentiation, its involvement in tissue regeneration is largely unknown. Here we show that EZH2 is up-regulated following cerulein-induced pancreatic injury and is required for tissue repair by promoting the regenerative proliferation of progenitor cells. Loss of EZH2 results in impaired pancreatic regeneration and accelerates KRas G12D -driven neoplasia. Our findings implicate EZH2 in constraining neoplastic progression through homeostatic mechanisms that control pancreatic regeneration and provide insights into the documented link between chronic pancreatic injury and an increased risk for pancreatic cancer.

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

“…The paradoxical role of EZH2 in tumorigenesis has been observed in several human cancers (16). Although its oncogenic role in promoting cancer progression has been well documented, in certain contexts it also can function as a tumor suppressor (17,20,(58)(59)(60)(61). In addition to leukemia, a tumor-suppressive role for EZH2 has been found in solid tumors such as pancreatic (61) and renal cancer (60).…”

Silencing of the Fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1

“…To date, no such regulation has been reported in the liver or white adipose tissue during chronic exposure to adverse conditions. Trimethylation of H3K27 is mediated by the polycomb repressor complex (PRC) 2 (3), and Enhancer of Zeste (EZH) 2, a component of the PRC2 complex (10), is believed to be an important regulator of acinar cell regeneration following pancreatitis (34). EZH2 is also increased in PDAC (31).…”

Role of Enhancer of Zeste Homolog 2 Polycomb Protein and Its Significance in Tumor Progression and Cell Differentiation

“…Subsequently, acinar cell mass and function is finally restored through redifferentiation, which corresponds to restored basal levels of EZH2. EZH2 is involved therefore in homeostatic mechanisms that controls pancreatic regeneration, decreasing the risk of pancreatic cancer in patient with chronic pancreatic injury [156,184].…”