ABSTRACT
Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment. However, in human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in breast cancer, especially in triple-negative breast cancer (TNBC). This facilitates the histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in breast cancer promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo breast cancer models including patient-derived TNBC xenograft, we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer. Together, this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.
ABSTRACT
Sepsis, the most common panthogeny, is characterized as multi-system injuries like immune system, inflammatory system and coagulation system, caused by systemic inflammatory response syndrome ( SIRS) and excessive oxidative stress after the invasion of pathogen.Severe cases can lead to multiple organ dysfunction syndrome and even death.Acute kidney injury is an independent risk factor which has an influence on patients'prognosis.Currently, the research of biomarkers of AKI is a significant field.Some new biomarkers are found to be charaterised by early appearance in blood or urine, non-traumatic and sensitivity in recent years, which contribute to their applications in early diagnosis of AKI.At present, the biomarkers of early diagnosis of AKI, such as calprotectin, interleukin-18, neutrophil gelatinase associated lipocalin (NGAL), cysteine protease inhibitor C, kidney injury molecule-1 (KIM-1) and cysteine rich 61, are under study.The current basic research and a few clinical studies show that these indicators may have a better sensitivity .