PHF14: an innate inhibitor against the progression of renal fibrosis following folic acid-induced kidney injury

Abstract

PHF14 is a newly identified regulator of mesenchyme growth in embryonic tissues. Previous studies have shown that phf14-null mutants die just after birth due to interstitial tissue hyperplasia in major organs, including the kidneys. The aim of this study was to investigate PHF14 function in renal fibrosis. By studying the chronic kidney injury mouse model, we found that PHF14 was upregulated in fibrotic kidneys after renal insults induced by folic acid administration. Compared with wild-type mice, PHF14-null mice showed more severe renal fibrosis after pro-fibrotic stimuli. Moreover, PHF14 in rat renal fibroblasts was upregulated by transforming growth factor-β (TGF-β) stimulation; while this upregulation was inhibited when smad3 phosphorylation was blocked. A chromatin immunoprecipitation (ChIP) assay further indicated that phospho-smad3 (p-smad3) acted as a transcription factor to enhance PHF14 expression. A lack of PHF14 expression enhanced collagen I and α-smooth muscle actin (α-SMA) synthesis induced by TGF-β in vitro. PHF14 was involved in inhibition of platelet-derived growth factor (PDGF) signaling overactivation by selectively repressing PDGF receptor-α (PDGFR-α) transcription. In summary, PHF14 expression was upregulated in fibrotic models in vivo and in vitro, and the TGF-β/smad3/PHF14 pathway acted as a self-limiting mechanism in the TGF-β-dominated renal pro-fibrotic process by suppressing PDGFR-α expression.

PHF14 enhances DNA methylation of SMAD7 gene to promote TGF-β-driven lung adenocarcinoma metastasis

“…In such a context, our present study identifies a PHF14/DNMT3B-mediated epigenetic mechanism via which SMAD7 transcription is suppressed in LAD. Consistently, previous studies have found that the expression of DNMT3B and PHF14 can be elevated following TGF-β stimulation 45 , 46 . Moreover, our data unveil that the transcriptional status of SMAD7 in LAD is jointly regulated by TGF-β signaling-mediated transcriptional activation and PHF14/DNMT3B-mediated transcriptional suppression.…”

The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways

“…Here, we report an additional interactor of HMG20A, the histone reader PHF14, which has also been associated with mesenchymal growth ( 16–18 ). Knockout of PHF14 in mice results in neonatal lethality due to defects in several organs including fibrosis in kidney and lung ( 16 , 19 ). We have now characterized the HMG20A-PHF14 complex molecularly and in silico and show that HMG20A and PHF14 share common functions in controlling the transcriptome, cell migration and invasion and cell-cell adhesion.…”

PHF14 Promotes Cell Proliferation and Migration through the AKT and ERK1/2 Pathways in Gastric Cancer Cells

“…Downregulation of PHF14 accelerates growth of BTC cells [23]. PHF14 inhibits renal fibrosis after kidney injury induced by folic acid [24]. Depletion of PHF14 inhibits cancer cell proliferation and tumorigenesis in lung cancer [25].…”