Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice. Pkd1 and Smyd2 doubleknockout mice lived longer than Pkd1-knockout mice. Targeting SMYD2 with its specific inhibitor, AZ505, delayed cyst growth in both early-and later-stage Pkd1 conditional knockout mouse models. SMYD2 carried out its function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased cystic renal epithelial cell proliferation and survival. We further identified two positive feedback loops that integrate epigenetic regulation and renal inflammation in cyst development: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. These pathways provide mechanisms by which SMYD2 might be induced by cyst fluid IL-6 and TNF-α in ADPKD kidneys. The SMYD2 transcriptional target gene Ptpn13 also linked SMYD2 to other PKD-associated signaling pathways, including ERK, mTOR, and Akt signaling, via PTPN13-mediated phosphorylation.

The Contribution of Histone Crotonylation to Tissue Health and Disease: Focus on Kidney Health

“…In this regard, the expression of the histone methyltransferase, EZH2, is increased in UUO and in CKD patients and its pharmacological inhibition reduced preclinical fibrosis (Zhou et al, 2016). Similar results were found for the histone methyltransferase, SMYD2 in clinical and preclinical PKD (Li et al, 2017). In AKI induced by IRI or endotoxin, increased histone methylation has been linked to the increased expression of proinflammatory and pro-fibrotic genes (Naito et al, 2008;Zager and Johnson, 2009).…”

Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression

“…Our previous ChIP-seq data indicated that PTPN13 was regulated by SMYD2 via the methylation of histones 29 , which regulates a variety of cellular processes and oncogenic transformation by removing phosphate groups from phosphorylated tyrosine residues on a number of proteins, including ERK and STAT 30 , 31 . SMYD2 is able to downregulate the expression of PTPN13 in TNBC cells (Supplementary Fig.…”

Functional analysis of the methyltransferase SMYD in the single-cell model organism Tetrahymena thermophila

“…responsible for protein-protein interactions with a prolinerich motif (PXLXP) (Arsenault et al 2016;Calpena et al 2015;Mazur et al 2016;Spellmon et al 2015). In mammals, there are five members of the SMYD family, SMYD1-5, with distinct biological functions (Al-Shar'i and Alnabulsi 2016; Bagislar et al 2016;Giakountis et al 2017;Li et al 2017;Spellmon et al 2015). SMYD1 is involved in cardiac development and in skeletal muscle growth and regeneration, by interacting with muscle-specific transcription factor skNAC or methylating histone H3K4 (Du et al 2014;Rasmussen et al 2015).…”

“…The lysine methyltransferase SMYD contains a conserved SET domain (Drosophila proteins Suppressor of variegation, Enhancer of Zeste, Trithorax) responsible for catalyzing lysine methylation (Herz et al 2013;Qian and Zhou 2006). This SET domain is interrupted by a MYND domain (Myeloid, Nervy and DEAF-1) (Al-Shar'i and Alnabulsi 2016; Calpena et al 2015;Li et al 2017) which is mainly Edited by Jiamei Li.…”