Histone methyltransferase MLL1 drives renal tubular cell apoptosis by p53-dependent repression of E-cadherin during cisplatin-induced acute kidney injury

Abstract

Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase that interacts with WD repeat domain 5 (WDR5) to regulate cell survival, proliferation, and senescence. The role of MLL1 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we demonstrate that MLL1, WDR5, and trimethylated H3K4 (H3K4me3) were upregulated in renal tubular cells of cisplatin-induced AKI in mice, along with increased phosphorylation of p53 and decreased expression of E-cadherin. Administration of MM102, a selective MLL1/WDR5 complex inhibitor, improved renal function and attenuated tubular injury and apoptosis, while repressing MLL1, WDR5, and H3K4me3, dephosphorylating p53 and preserving E-cadherin. In cultured mouse renal proximal tubular cells (RPTCs) exposed to cisplatin, treatment with MM102 or transfection with siRNAs for either MLL1 or WDR5 also inhibited apoptosis and p53 phosphorylation while preserving E-cadherin expression; p53 inhibition with Pifithrin-α lowered cisplatin-induced apoptosis without affecting expression of MLL1, WDR5, and H3K4me3. Interestingly, silencing of E-cadherin offset MM102’s cytoprotective effects, but had no effect on p53 phosphorylation. These findings suggest that MLL1/WDR5 activates p53, which, in turn, represses E-cadherin, leading to apoptosis during cisplatin-induced AKI. Further studies showed that MM102 effectively inhibited cisplatin-triggered DNA damage response (DDR), as indicated by dephosphorylation of ataxia telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR) proteins, dephosphorylation of checkpoint kinase 1 and 2 (Chk1 and Chk2); depression of γ-H2AX; and restrained cell cycle arrest, as evidenced by decreased expression of p21 and phospho-histone H3 at serine 10 in vitro and in vivo. Overall, we identify MLL1 as a novel DDR regulator that drives cisplatin-induced RPTC apoptosis and AKI by modulating the MLL1/WDR5-/ATR/ATM-Chk-p53-E-cadherin axis. Targeting the MLL1/WDR5 complex may have a therapeutic potential for the treatment of AKI.

Lycorine (Lycoris radiata)- A unique natural medicine on breast cancer

“…The phosphorylation of p-H3 is catalyzed by mitotic kinases, such as Aurora A and Aurora B, which recognize and bind to the p-H3 modi ed histones. Any disruptions in p-H3 phosphorylation levels may lead to a variety of chromosomal abnormalities and contribute to the development of diseases such as cancer [27]. Herein, the down-regulated expressions of protein Aurora A and Aurora B induced by lycorine in this study revealed in this study.…”

Histone methyltransferase SET8 aggravates acute kidney injury through activation of p53 and downregulation of PTEN

“…Apoptosis is an essential process that removes damaged cells while leaving normal cells unharmed [31] and it also plays a vital role in regulating kidney disease [20,29]. In our previous studies, we found that atypical expression and activation of histone methyltransferases, such as EZH2 and MLL1, are associated with cisplatin-induced AKI and renal epithelial cell apoptosis [11][12][13]. However, it is still unknown if other histone methyltransferases are involved in these pathological processes.…”

“…Previous studies reveal an autoregulatory loop between PTEN and p53 during cell cycle arrest [38]. p53 is a major downstream mediator of DNA damage response during cisplatin-induced AKI [11]. Although PTEN is mainly found in the cytoplasm, and p53 is predominantly in the nucleus, there is direct functional crosstalk between them.…”

“…Previous study indicates that p53 phosphorylation is vital in promoting the transcription of speci c apoptosis-related proteins in cisplatin-induced AKI [11,12], and related to cisplatin induced DNA damage and cell cycle arrest [23,24]. To explore the involvement of SET8 in DNA damage and cell cycle arrest and in relation to p53, we examined p53 phosphorylation and expression levels of p-H2A and p21.…”

“…Our recent studies showed that the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is essential for the silencing of PTEN in the brotic injured kidney and the repression of renal Ecadherin in IR and folic acid-induced AKI in murine models. Similarly, activation of mixed lineage leukemia (MLL1) another histone transferase results in the downregulation of renal E-cadherin in cisplatin-induced AKI and apoptosis of renal epithelial tubular cells [11][12][13]. In addition to EZH2 and MLL1, other histone methyltransferases are also expressed in the kidney [14].…”