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Estrogen receptor alpha (ERα) is a ligand-activated transcription factor. Upon estrogen stimulation, ERα recruits a number of coregulators, including both coactivators and corepressors, to the estrogen response elements, modulating gene activation or repression. Most coregulator complexes contain histone-modifying enzymes to control ERα target gene expression in an epigenetic manner. In addition to histones, these epigenetic modifiers can modify nonhistone proteins including ERα, thereby constituting another layer of transcriptional regulation. Here we show that SET and MYND domain containing 2 (SMYD2), a histone H3K4 and H3K36 methyltransferase, directly methylates ERα protein at lysine 266 (K266) both in vitro and in cells. In breast cancer MCF7 cells, SMYD2 attenuates the chromatin recruitment of ERα to prevent ERα target gene activation under an estrogen-depleted condition. Importantly, the SMYD2-mediated repression of ERα target gene expression is mediated by the methylation of ERα at K266 in the nucleus, but not the methylation of histone H3K4. Upon estrogen stimulation, ERα-K266 methylation is diminished, thereby enabling p300/cAMP response element-binding protein-binding protein to acetylate ERα at K266, which is known to promote ERα transactivation activity. Our study identifies a previously undescribed inhibitory methylation event on ERα. Our data suggest that the dynamic cross-talk between SMYD2-mediated ERα protein methylation and p300/cAMP response element-binding protein-binding protein-dependent ERα acetylation plays an important role in fine-tuning the functions of ERα at chromatin and the estrogen-induced gene expression profiles.ERα hinge region | lysine methylation | LSD1 E strogen receptors (ERs) are a subfamily of nuclear receptors that control cellular responses to estrogens (1). There are two different forms of ER, usually referred to as ERα and ERβ, and ERα is the dominant form expressed in breast and ovary tissues. The regulation of hormone-responsive gene expression by ERα as well as other nuclear receptors is a complex process involving a variety of cellular responses. One essential step is the recruitment of transcriptional coregulators-namely, nuclear receptor coactivators (NCOAs; also known as steroid receptor coactivators; e.g., SRC1, 2, and 3) or nuclear receptor corepressors (NCORs)-in a hormone-dependent manner (2). Most coactivator complexes comprise histone lysine (K) acetyltransferases such as p300/cAMP response element-binding protein-binding protein (CBP) (3), which can put on acetylation marks on histones. Histone acetylation helps open up chromatin around the estrogen response element (ERE) regions to facilitate the loading of RNA polymerase II transcriptional machinery. In the absence of its hormone ligands, ERα interacts with corepressor complexes, which normally consist of histone deacetylases (HDACs), to remove acetylation on histones, leading to gene repression (4).In addition to modifying histones, these nuclear receptor coregulators can modify nonhistone proteins, ...

This study suggested that LL-37 may play important role in the pathogenesis of COPD and may be a possible novel therapeutic target in COPD.

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Histone lysine demethylases (KDMs) comprise a large class of enzymes that catalyze site-specific demethylation of lysine residues on histones and other proteins. They play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of KDMs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of 24 KDMs in breast cancer and identified associations among recurrent copy number alterations, gene expression, breast cancer subtypes, and clinical outcome. Two KDMs, KDM2A and KDM5B, had the highest frequency of genetic amplification and overexpression. Furthermore, among the 24 KDM genes, KDM2A had the highest correlation between copy number and mRNA expression, and high mRNA levels of KDM2A were significantly associated with shorter survival of breast cancer patients. KDM2A has two isoforms: the long isoform is comprised of a JmjC domain, CXXC-zinc finger, PHD zinc finger, F-box, and the AMN1 protein domain; whereas the short isoform of KDM2A lacks the N-terminal JmjC domain but contains all other motifs. Detailed characterization of KDM2A in breast cancer revealed that the short isoform of KDM2A is more abundant than the long isoform at DNA, mRNA, and protein levels in a subset of breast cancers. Furthermore, our data indicate that the short isoform of KDM2A has oncogenic potential and functions as an oncogenic isoform in a subset of breast cancers. Taken together, our findings suggest that amplification and overexpression of the KDM2A short isoform is critical in breast cancer progression.

SmyD2 belongs to a new class of chromatin regulators that control gene expression in heart development and tumorigenesis. Besides methylation of histone H3 K4, SmyD2 can methylate non-histone targets including p53 and the retinoblastoma tumor suppressor. The methyltransferase activity of SmyD proteins has been proposed to be regulated by autoinhibition via the intra- and interdomain bending of the conserved C-terminal domain (CTD). However, there has been no direct evidence of a conformational change in the CTD. Here, we report two crystal structures of SmyD2 bound either to the cofactor product S-adenosylhomocysteine or to the inhibitor sinefungin. SmyD2 has a two-lobed structure with the active site located at the bottom of a deep crevice formed between the CTD and the catalytic domain. By extensive engagement with the methyltransferase domain, the CTD stabilizes the autoinhibited conformation of SmyD2 and restricts access to the catalytic site. Unexpectedly, despite that the two SmyD2 structures are highly superimposable, significant differences are observed in the first two helices of the CTDs: the two helices bend outwards and move away from the catalytic domain to generate a less closed conformation in the sinefungin-bound structure. Although the overall fold of the individual domains is structurally conserved among SmyD proteins, SmyD2 appear to be a conformational “intermediate” between a close form of SmyD3 and an open form of SmyD1. In addition, the structures reveal that the CTD is structurally similar to tetratricopeptide repeats (TPR), a motif through which many cochaperones bind to the heat shock protein Hsp90. Our results thus provide the first evidence for the intradomain flexibility of the TPR-like CTD, which may be important for the activation of SmyD proteins by Hsp90.

Background:Pulmonary carcinoids (PC) are histologically classified into typical carcinoid (TC) and atypical carcinoid (AC). The diagnosis of pulmonary carcinoid and possibly the differentiation between TC and AC could make a significant effect on the treatment planning as well as prognosis.[1] Several studies have explored the utility of 68Ga-DOTA-Peptide (68Ga-labelled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-peptide) and 18F-flurodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the evaluation of primary pulmonary carcinoids. Therefore, we performed a meta-analysis to evaluate the diagnostic accuracy and prediction efficiency of histological subtypes of these two imaging modalities in primary PC.Methods:Relevant studies were identified by searching PubMed, Web of Science, and EMBASE published from 2006 to 2016. Two authors extracted characteristics of patients and their lesions using predefined criteria.Results:Fourteen studies comprising 352 patients were included in this meta-analysis. The pooled sensitivity of 68Ga-DOTA-Peptide and 18F-FDG PET/CT in detecting pulmonary carcinoid were 90.0% (95% CI = 82.0–95.0%; P = .07; I2 = 49.6%) and 71.0% (95% CI = 66.0–76.0%; P < .001; I2 = 59.3%), respectively. An SUVmax ratio between 68Ga-DOTA-Peptide and 18F-FDG higher than the cutoff value of 4.28 was predictive of TC with 89.3% sensitivity and 100% specificity (AUC, 96.4%; 95% CI, 91.1–100%). The ratio of tumor uptake to atelectatic lung uptake was significantly higher for 68Ga-DOTA-peptide (2.5–91, mean 30.5 ± 28.1) than for 18F-FDG (0.3–10.3, mean 2.1 ± 2.3) (P < .001).Conclusions:Both 68Ga-DOTA-peptide and 18F-FDG are highly sensitive in detecting pulmonary carcinoid, while 68Ga-DOTA-peptide is more sensitive than 18F-FDG (90.0% vs 71.0%). The SUVmax ratio was an accurate predictor of the histopathologic variety of the carcinoid tumor, and 68Ga-DOTA-peptide was better than 18F-FDG in cases with atelectasis.