HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer

Abstract

Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysinespecific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with Kras G12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. We also identify a subset of nonclassical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumorsuppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.

Lysine Demethylase KDM6A in Differentiation, Development, and Cancer

“…HNF1A is a homeodomain transcription factor that had been thought to be a pancreatic tumor suppressor. It was also shown that HNF1A loss partially phenocopies KDM6A KO in Kras G12Dinduced pancreatic cancer (20). KDM6A also plays a role in suppressing myeloid leukemogenesis independently of its demethylase activity.…”

“…The mechanism behind KDM6A genomic targeting also requires further investigation. It has been hinted that certain TFs could interact with KDM6A, which, in turn, recruits MLL3/4 to activate enhancers (20,24).…”

“…More recent studies found that the TPR domains were necessary to facilitate KDM6A's association with the MLL3/4 complex. In particular, either the deletion of TPR domains or point mutations (G137V and D336G) in the TPR domains significantly reduce KDM6A's physical interactions with the MLL3/4 complex (19,20).…”

Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer

“…HNF1A is a transcription factor that regulates the differentiation of endodermal genes and regulates the acinar cell identity. Aberrant expression of HNF1A alters lineage differentiation, growth, and the acinar cell plasticity via binding at the enhancers of several acinar genes [48]. HNF1A has been linked to tumor suppressive role based on tumor expression [49,50] but has been recently identified to promote cancer stemness [16] and resistance to paclitaxel and tyrosine kinase inhibitors [10] in pancreatic tumorigenesis.…”

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.…”