Blocking the road to de‐differentiation: HNF 1A/ KDM 6A complex safeguards epithelial integrity in pancreatic cancer

Abstract

Epithelial differentiation of normal and tumor cells is orchestrated by lineage‐determining transcriptional regulatory networks that enforce cell identity. Recent research by Kalisz et al (2020) in the EMBO Journal elucidates the molecular mechanisms by which a transcriptional differentiation program governed by HNF1A and KDM6A maintains acinar differentiation and the epithelial identity of pancreatic ductal adenocarcinoma (PDAC). Loss of function of either transcriptional regulator induces tumor progression to a poorly differentiated and highly aggressive PDAC subtype with a squamous transcriptome and poor prognosis.

The SUMO pathway in pancreatic cancer: insights and inhibition

“…6 The basal-like subtype is characterised by activation of the MYC pathway together with pro-inflammatory pathways, hypoxia networks, metabolic reprogramming, autophagy, epidermal growth factor and transforming growth factor-β (TGF-β) signalling and activation of the ΔNp63 pathway, 3 as well as being enriched in mutations in the tumour-suppressor TP53 and the lysine demethylase KDM6A and showing silencing of endodermal identity transcription factors, such as GATA6 or hepatocyte nuclear factor family members. 3,[6][7][8][9][10][11] The clear differences in the molecular underpinnings of the PDAC subtypes illustrate that understanding the biological mechanisms that drive these subtypes and connect the different subtypes with novel therapies represents one promising approach to improve the outcome of the disease.…”