Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes

FOXA2 has been known to play important roles in liver functions in rodents. However, its role in human hepatocytes is not fully understood. Recently, we generated FOXA2 mutant induced pluripotent stem cell (FOXA2^−/−iPSC) lines and illustrated that loss of FOXA2 results in developmental defects in pancreatic islet cells. Here, we used FOXA2^−/−iPSC lines to understand the role of FOXA2 on the development and function of human hepatocytes. Lack of FOXA2 resulted in significant alterations in the expression of key developmental and functional genes in hepatic progenitors (HP) and mature hepatocytes (MH) as well as an increase in the expression of ER stress markers. Functional assays demonstrated an increase in lipid accumulation, bile acid synthesis and glycerol production, while a decrease in glucose uptake, glycogen storage, and Albumin secretion. RNA-sequencing analysis further validated the findings by showing a significant increase in genes associated with lipid metabolism, bile acid secretion, and suggested the activation of hepatic stellate cells and hepatic fibrosis in MH lacking FOXA2. Overexpression of FOXA2 reversed the defective phenotypes and improved hepatocyte functionality in iPSC-derived hepatic cells lacking FOXA2. These results highlight a potential role of FOXA2 in regulating human hepatic development and function and provide a human hepatocyte model, which can be used to identify novel therapeutic targets for FOXA2-associated liver disorders.Subject terms: Induced pluripotent stem cells, Stem-cell differentiation     

FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma

Lung cancer remains one of the most common malignancies and the leading cause of cancer-related death worldwide. Forkhead box protein A1 (FOXA1) is a pioneer factor amplified in lung adenocarcinoma (LUAD). However, its role in LUAD remains elusive. In this study, we found that expression of FOXA1 enhanced LUAD cell survival in nutrients deprived conditions through inhibiting autophagic cell death (ACD). FOXA1 bound to the imprinting control region of insulin-like growth factor 2 (IGF2) and interacted with DNA methyltransferase 1 (DNMT1), leading to initiation of DNMT1-mediated loss of imprinting (LOI) of IGF2 and autocrine of IGF2. Blockage of IGF2 and its downstream insulin-like growth factor 1 receptor (IGF1R) abolished the protective effect of FOXA1 on LUAD cells in nutrients deprived conditions. Furthermore, FOXA1 suppressed the expression of the lysosomal enzyme glucocerebrosidase 1 (GBA1), a positive mediator of ACD, through ubiquitination of GBA1 enhanced by IGF2. Notably, FOXA1 expression in A549 cells reduced the efficacy of the anti-angiogenic drug nintedanib to inhibit xenograft tumor growth, whereas a combination of nintedanib with IGF1R inhibitor linsitinib or mTORC1 inhibitor rapamycin enhanced tumor control. Clinically, high expression level of FOXA1 protein was associated with unfavorable prognosis in LUAD patients of advanced stage who received bevacizumab treatment. Our findings uncovered a previously unrecognized role of FOXA1 in mediating loss of imprinting of IGF2, which confer LUAD cells enhanced survival ability against nutrients deprivation through suppressing autophagic cell death.Subject terms: Non-small-cell lung cancer, Targeted therapies