The role and prospect of lysine‐specific demethylases in cancer chemoresistance

Abstract

Histone methylation plays a key function in modulating gene expression, and preserving genome integrity and epigenetic inheritance. However, aberrations of histone methylation are commonly observed in human diseases, especially cancer. Lysine methylation mediated by histone methyltransferases can be reversed by lysine demethylases (KDMs), which remove methyl marks from histone lysine residues. Currently, drug resistance is a main impediment for cancer therapy. KDMs have been found to mediate drug tolerance of many cancers via altering the metabolic profile of cancer cells, upregulating the ratio of cancer stem cells and drug‐tolerant genes, and promoting the epithelial‐mesenchymal transition and metastatic ability. Moreover, different cancers show distinct oncogenic addictions for KDMs. The abnormal activation or overexpression of KDMs can alter gene expression signatures to enhance cell survival and drug resistance in cancer cells. In this review, we describe the structural features and functions of KDMs, the KDMs preferences of different cancers, and the mechanisms of drug resistance resulting from KDMs. We then survey KDM inhibitors that have been used for combating drug resistance in cancer, and discuss the opportunities and challenges of KDMs as therapeutic targets for cancer drug resistance.

The Unique Role of the Second Coordination Sphere to Unlock and Control Catalysis in Nonheme Fe(II)/2-Oxoglutarate Histone Demethylase KDM2A

“…KDM2A is the first known JmjC demethylase (Figure S1), identified specifically to demethylase lower (monomethylated and demethylated) methylation states of histone H3 lysine 36 (H3K36me1 and H3K36me2) to formaldehyde and succinate. , KDM2A is found in the nucleus and is expressed in several tissues, especially in the brain, lungs, ovaries, and testis, and it is also involved in the alternative lengthening of telomeres. − Altered KDM2A gene expression affects several cancers, significantly in lung, breast, and ovarian cancer; ,,− therefore, the enzyme is a target for drug design. The overall catalytic mechanism of KDM2A is similar to other KDMs and other Fe­(II)/2OG enzymes; the reaction starts with binding dioxygen to the Fe·20G·substrate complex to form a ferric Fe­(III)-superoxo complex. − The reaction proceeds through the oxidative decarboxylation of 2OG to form succinate and ferryl Fe­(IV)O intermediates.…”