Hepatic HDAC3 Regulates Systemic Iron Homeostasis and Ferroptosis via the Hippo Signaling Pathway

Histone deacetylases(HDACs)are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis.However,whether and how HDACs regulate iron metabolism and ferroptosis(an iron-dependent form of cell death)remain unclear.Here,the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse models.Mice lacking Hdac3 expression in the liver(Hdac3-LKO mice)have significantly reduced hepatic Hamp mRNA(encoding the peptide hormone hepcidin)and altered iron homeostasis.Transcription profiling of Hdac3-LKO mice suggests that the Hippo signaling pathway may be downstream of Hdac3.Moreover,using a Hippo pathway inhibitor and overexpressing the transcriptional regulator Yap(Yes-associated protein)significantly reduced Hamp mRNA levels.Using a promoter reporter assay,we then identified 2 Yap-binding repressor sites within the human HAMP promoter region.We also found that inhibiting Hdac3 led to increased translocation of Yap to the nucleus,suggesting activation of Yap.Notably,knock-in mice expressing a constitutively active form of Yap(Yap K342M)phenocopied the altered hepcidin levels observed in Hdac3-LKO mice.Mechanistically,we show that iron-overload-induced ferroptosis underlies the liver injury that develops in Hdac3-LKO mice,and knocking down Yap expression in Hdac3-LKO mice reduces both iron-overload-and ferroptosis-induced liver injury.These results provide compelling evidence supporting the notion that HDAC3 regulates iron homeostasis via the Hippo/Yap pathway and may serve as a target for reducing ferroptosis in iron-overload-related diseases.

The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2

Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.

Rewiring ERBB3 and ERK signaling confers resistance to FGFR1 inhibition in gastrointestinal cancer harbored an ERBB3-E928G mutation

Dear Editor,Recently,a large number of studies found that activation of ERBB3(Erb-B2 receptor tyrosine kinase 3,also known as HER3)may be one of the major mechanisms underlying resistance to therapies that target the EGFR(epidermal growth factor receptor),HER2,and other receptor tyrosine kinases(RTKs)(Chen et al.,2011;Choi et al.,2012;Ross et al.,2018).Interestingly,mutations in ERBB3 are commonly reported in gastrointestinal(Gl)cancer,with mutations identified in approximately 12%of stomach and colorectal cancer cases(Jaiswal et al.,2013).

Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma

Despite recent advances in the management and treatment of esophageal squamous cell carcinoma(ESCC),the prognosis remains extremely poor,and current nonsurgical treatment options are limited.To identify new therapeutic targets,we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth;similar results were obtained by knocking down both LSD1 and G9a expression.Importantly,we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines.To examine the clinical relevance of these findings,we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues,and this increased expression was significantly correlated with poor prognosis.Mechanistically,we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis,and cotargeting ER stress pathways increased this effect both in vitro and in vivo.Taken together,these findings provide compelling evidence that targeting LSD1,G9a,and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.