Reduction in H3K4me patterns due to aberrant expression of methyltransferases and demethylases in renal cell carcinoma: prognostic and therapeutic implications

Abstract

Renal cell carcinoma (RCC) is the leading cause among cancer-related deaths due to urological cancers, which results in response to combination of genetic and epigenetic factors. Histone methylations have been implicated in renal tumorigenesis but their clinical significance and underlying pathology are unexplored. Here, we elucidated the histone 3 lysine 4 (H3K4) methylation patterns in clear cell RCC and its underlying pathology. Lower cellular levels of H3K4 mono-methylation, -dimethylation and –tri-methylation were fraternized with higher TNM staging and Fuhrman grading as well as tumor metastasis. Further, the expression profile of 20 H3K4 modifiers revealed the significant over-expression of histone demethylases compared to methyltransferases, indicating their role in the reduction of H3K4 methylation levels. In view of above facts, the role of LSD2 and KDM5A demethylases in RCC pathogenesis were explored using respective siRNAs. The RCC cells exhibited reduced cell viability after knockdown of LSD2 and KDM5A genes with concomitant induction of apoptosis. In addition, propidium iodide staining demonstrated an arrest of RCC cells at S-phase and sub-G1 phase of the cell cycle. Taken together, these observations provide new pathological insights behind the alterations of H3K4 methylation patterns in ccRCC with their prognostic and therapeutic implications.

H3K4me3 Is a Potential Mediator for Antiproliferative Effects of Calcitriol (1α,25(OH)2D3) in Ovarian Cancer Biology

“…The present H3K4me3 expression analysis elucidated that high expression levels are correlated with better clinical outcomes being in agreement with previous observation of the prognostic significance of H3K4me3 in renal cell carcinoma [10]. Kumar et al reported that H3K4me3 level was significantly decreased in metastasis of renal cell carcinoma and therefore suggested the implication as a biomarker to discriminate metastatic from nonmetastatic tumors [11]. In contrast, other reports suggested that increased H3K4me3 expression was associated with impaired overall survival in various cancers, such as hepatocellular carcinoma [38], cervical cancer [39], and early-stage colon cancer [8].…”

“…Meanwhile, immunocytochemistry (ICC) is also applied to confirm histone H3 modification expression in normal and cancer cells [5,7]. Former studies have reported that alteration in the histone modification patterns can provide prognostic information for several cancers, including those detected in colon [8,9], kidney [10,11], lung [5,12], stomach [13], pancreas [14,15], ovary [14], and breast [14,16].…”

The emerging role of KDM5A in human cancer

“…Renal cell carcinoma (RCC) is a leading cause of death among urological cancers. KDM5A facilitates cell proliferation and metastasis via reducing methylated H3K4 [ 107 ]. Silencing KDM5A leads to the induction of apoptosis and cell cycle arrest [ 107 ].…”

“…KDM5A facilitates cell proliferation and metastasis via reducing methylated H3K4 [ 107 ]. Silencing KDM5A leads to the induction of apoptosis and cell cycle arrest [ 107 ]. KDM5A is also a prognostic indicator for RCC, and it promotes EMT to induce stemness in tumor cells [ 47 ].…”

Methylation-directed Acetylation of Histone H3 Regulates Developmental Sensitivity to Histone Deacetylase Inhibition

“…This overexpression it has been proposed to lead to upregulation of expression of the oncogene c-myc, for example in hepatocellular carcinomas [49]. It will be informative to investigate whether these cells show altered sensitivity to hydroxamates and whether other components of this pathway such as reduced levels of H3K4me3 seen in some cancers, could also provide biomarkers for resistance [50,51].…”