Peptide Inhibitor Targeting the Extraterminal Domain in BRD4 Potently Suppresses Breast Cancer Both and .

BRD4 is associated with a variety of human diseases, including breast cancer. The crucial roles of amino-terminal bromodomains (BDs) of BRD4 in binding with acetylated histones to regulate oncogene expression make them promising drug targets. However, adverse events impede the development of the BD inhibitors.

ER-localized JmjC domain-containing protein JMJD8 targets STING to promote immune evasion and tumor growth in breast cancer.

The STING-mediated type I interferon (IFN) signaling pathway has been shown to play critical roles in antitumor immunity. Here, we demonstrate that an endoplasmic reticulum (ER)-localized JmjC domain-containing protein, JMJD8, inhibits STING-induced type I IFN responses to promote immune evasion and breast tumorigenesis. Mechanistically, JMJD8 competes with TBK1 for binding with STING, blocking STING-TBK1 complex formation and restricting type I IFN and IFN-stimulated gene (ISG) expression as well as immune cell infiltration.

A specific JMJD6 inhibitor potently suppresses multiple types of cancers both in vitro and in vivo.

Jumonji C-domain-containing protein 6 (JMJD6), an iron (Fe) and α-ketoglutarate (α-KG)-dependent oxygenase, is expressed at high levels, correlated with poor prognosis, and considered as a therapeutic target in multiple cancer types. However, specific JMJD6 inhibitors that are potent in suppressing tumorigenesis have not been reported so far. We herein report that iJMJD6, a specific small-molecule inhibitor of JMJD6 with favorable physiochemical properties, inhibits the enzymatic activity of JMJD6 protein both in vitro and in cultured cells.

A hypermethylation strategy utilized by enhancer-bound CARM1 to promote estrogen receptor α-dependent transcriptional activation and breast carcinogenesis.

While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their functions and the underlying molecular mechanisms in cancers, particularly in estrogen receptor alpha (ERα)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) in ERα-positive breast cancers due to its high expression and the associated poor prognosis. : ChIP-seq and RNA-seq were employed to identify the chromatin-binding landscape and transcriptional targets of CARM1, respectively, in the presence of estrogen in ERα-positive MCF7 breast cancer cells.

In Silico Discovery of JMJD6 Inhibitors for Cancer Treatment.

The 2-oxoglutarate (2OG)-dependent oxygenase JMJD6 is emerging as a potential anticancer target, but its inhibitors have not been reported so far. In this study, we reported an in silico protocol to discover JMJD6 inhibitors targeting the druggable 2OG-binding site. Following this protocol, one compound, which we named as WL12, was found to be able to inhibit JMJD6 enzymatic activity and JMJD6-dependent cell proliferation.

Regulation of Transcription Factor Yin Yang 1 by SET7/9-mediated Lysine Methylation.

Yin Yang 1 (YY1) is a multifunctional transcription factor shown to be critical in a variety of biological processes. Although it is regulated by multiple types of post-translational modifications (PTMs), whether YY1 is methylated, which enzyme methylates YY1, and hence the functional significance of YY1 methylation remains completely unknown. Here we reported the first methyltransferase, SET7/9 (KMT7), capable of methylating YY1 at two highly conserved lysine (K) residues, K173 and K411, located in two distinct domains, one in the central glycine-rich region and the other in the very carboxyl-terminus.

Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation.

Although "histone" methyltransferases and demethylases are well established to regulate transcriptional programs and to use nonhistone proteins as substrates, their possible roles in regulation of heat-shock proteins in the nucleus have not been investigated. Here, we report that a highly conserved arginine residue, R469, in HSP70 (heat-shock protein of 70 kDa) proteins, an evolutionarily conserved protein family of ATP-dependent molecular chaperone, was monomethylated (me1), at least partially, by coactivator-associated arginine methyltransferase 1/protein arginine methyltransferase 4 (CARM1/PRMT4) and demethylated by jumonji-domain-containing 6 (JMJD6), both in vitro and in cultured cells. Functional studies revealed that HSP70 could directly regulate retinoid acid (RA)-induced retinoid acid receptor β2 (RARβ2) gene transcription through its binding to chromatin, with R469me1 being essential in this process.

Using auto covariance method for functional discrimination of membrane proteins based on evolution information.

Membrane transporters are critical in living cells. Therefore, the discrimination of the types of membrane proteins based on their functions is of great importance both for helping genome annotation and providing a supplementary role to experimental researchers to gain insight into membrane proteins' function. There are a lot of computational methods to facilitate the identification of the functional types of membrane proteins.

Using the augmented Chou's pseudo amino acid composition for predicting protein submitochondria locations based on auto covariance approach.

The submitochondria location of a mitochondrial protein is very important for further understanding the structure and function of this protein. Hence, it is of great practical significance to develop an automated and reliable method for timely identifying the submitochondria locations of novel mitochondrial proteins. In this study, a sequence-based algorithm combining the augmented Chou's pseudo amino acid composition (Chou's PseAA) based on auto covariance (AC) is developed to predict protein submitochondria locations and membrane protein types in mitochondria inner membrane.