ABSTRACT
It has been well established that the von Hippel-Lindau/hypoxia-inducible factor α (VHL-HIFα) axis and epidermal growth factor receptor (EGFR) signaling pathway play a critical role in the pathogenesis and progression of renal cell carcinoma (RCC). However, few studies have addressed the relationship between the two oncogenic drivers in RCC. SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase involved in gene transcription and oncogenesis, but its expression and function in RCC remain unclear. In the present study, we found that SMYD3 expression was significantly elevated in RCC tumors and correlated with advanced tumor stage, histological and nuclear grade, and shorter survival. Depletion of SMYD3 inhibited RCC cell proliferation, colony numbers, and xenograft tumor formation, while promoted apoptosis. Mechanistically, SMYD3 cooperates with SP1 to transcriptionally promote EGFR expression, amplifying its downstream signaling activity. TCGA data analyses revealed a significantly increased SMYD3 expression in primary RCC tumors carrying the loss-of-function VHL mutations. We further showed that HIF-2α can directly bind to the SMYD3 promoter and subsequently induced SMYD3 transcription and expression. Taken together, we identify the VHL/HIF-2α/SMYD3 signaling cascade-mediated EGFR hyperactivity through which SMYD3 promotes RCC progression. Our study suggests that SMYD3 is a potential therapeutic target and prognostic factor in RCC.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Carcinoma, Renal Cell/metabolism , Gene Expression Regulation, Neoplastic , Histone-Lysine N-Methyltransferase/biosynthesis , Kidney Neoplasms/metabolism , Neoplasm Proteins/metabolism , Signal Transduction , Transcriptional Activation , Up-Regulation , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , ErbB Receptors/biosynthesis , ErbB Receptors/genetics , Histone-Lysine N-Methyltransferase/genetics , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Proteins/genetics , Von Hippel-Lindau Tumor Suppressor Protein/geneticsABSTRACT
A novel Eu-based MOF [Eu(IMS1)2]Cl·4H2O (1) was successfully constructed based on a semi-rigid zwitterionic 1,3-bis(4-carboxylbenzyl)-imidazolium (IMS1) ligand, featuring a 3-fold interpenetrating dia net structure with a point symbol of 66 and charged permanent micropores. Considering its excellent luminescent property as well as thermal and chemical stability, complex 1 was explored as a potential sensor for detecting Fe3+ ions. The results show that complex 1 has a high sensitivity and selectivity for Fe3+ based on a 'turn-off' effect, for which the electrostatic interaction between Fe3+ ions and the inner surface of the micropores may play a critical role. The fluorescence quenching mechanism reveals that dynamic quenching and competitive adsorption between Fe3+ and 1 lead to the quenching effect of 1.
