WDR61 ablation triggers R-loop accumulation and suppresses breast cancer progression.

Although, superkiller complex protein 8 (SKI8), previously known as WDR61 has been identified and mapped in breast tumor, little is currently known about its function. This study aims to elucidate the role of WDR61 in breast tumor development and its potential as a therapeutic target. Here, we show that tamoxifen-induced knockout of Wdr61 reduces the risk of breast tumors, resulting in smaller tumor size and weight, and improved overall survival. Furthermore, we show that knockdown of WDR61 compromises the proliferation of breast tumor cells with reduced colony-forming capacity. Further investigations demonstrate that the protective effect of WDR61 loss on breast tumor development is due to genomic instability. Mechanistic studies reveal that WDR61 interacts with the R-loop, and loss of WDR61 leads to R-loops accumulation in breast tumor cells, causing DNA damage and subsequent inhibition of cell proliferation. In summary, this study highlights the critical dependence of breast tumors on WDR61, which suppresses R-loop and counteracts endogenous DNA damage in tumor cells.

Inhibition of α1-adrenoceptor reduces TGF-ß1-induced epithelial-to-mesenchymal transition and attenuates UUO-induced renal fibrosis in mice.

Renal fibrosis is a common pathological hallmark of chronic kidney disease (CKD). Renal sympathetic nerve activity is elevated in patients and experimental animals with CKD and contributes to renal interstitial fibrosis in obstructive nephropathy. However, the mechanisms underlying sympathetic overactivation in renal fibrosis remain unknown. Norepinephrine (NE), the main sympathetic neurotransmitter, was found to promote TGF-ß1-induced epithelial-mesenchymal transition (EMT) and fibrotic gene expression in the human renal proximal epithelial cell line HK-2. Using both genetic and pharmacological approaches, we identified that NE binds Gαq-coupled α1-adrenoceptor (α1-AR) to enhance EMT of HK-2 cells by activating p38/Smad3 signaling. Inhibition of p38 diminished the NE-exaggerated EMT process and increased the fibrotic gene expression in TGF-ß1-treated HK-2 cells. Moreover, the pharmacological blockade of α1-AR reduced the kidney injury and renal fibrosis in a unilateral ureteral obstruction mouse model by suppressing EMT in the kidneys. Thus, sympathetic overactivation facilitates EMT of renal epithelial cells and fibrosis via the α1-AR/p38/Smad3 signaling pathway, and α1-AR inhibition may be a promising approach toward treating renal fibrosis.