SUMMARY Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC domain-containing proteins in mediating enhancer activation remain poorly understood. Here we report that recruitment of the JmjC domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 was found to interact with MED12 in the mediator complex to regulate its recruitment. Unexpectedly, JMJD6 is necessary for MED12 to interact with CARM1, which methylates MED12 at multiple arginine sites and regulates its chromatin binding. Consistent with its role in transcriptional activation, JMJD6 is required for estrogen/ERα-induced breast cancer cell growth and tumorigenesis. Our data have uncovered a critical regulator of estrogen/ERα-induced enhancer, coding gene activation and breast cancer cell potency, providing a potential therapeutic target of ER-positive breast cancers.

Dihydroartemisinin (DHA), the main active metabolite of artemisinin derivatives, is one of the most effective anti-malarial analogs of artemisinin. In the current study, we found that DHA inhibited the proliferation of a panel of tumor cells originated from different tissue types. DHA effectively induced apoptosis in human promyelocytic leukemia HL-60 cells, which was accompanied with mitochondrial dysfunction and caspases activation. Further studies indicated that DHA-induced apoptosis was iron-dependent. Though DHA slightly elicited superoxide anion, these reactive oxygen species (ROS) contribute little to DHA-induced apoptosis in HL-60 cells. Moreover, DHA time-dependently activated mitogen-activeted protein kinases (MAPKs) and specific inhibition of p38 MAPK, but not c-Jun-NH2-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK), abolished DHA-induced apoptosis, indicating that activation of p38 MAPK is required for DHA-induced apoptosis in HL-60 cells. Altogether, our data uncover that DHA induces apoptosis is dependent of iron and p38 MAPK activation but not ROS in HL-60 cells.

Scorpions and their venoms have been used in traditional medicine for thousands of years in China, India and Africa. The scorpion venom is a highly complex mixture of salts, nucleotides, biogenic amines, enzymes, mucoproteins, as well as peptides and proteins (e.g. neurotoxins). One of the recently observed biological properties of animal venoms and toxins is that they possess anticancer potential. An increasing number of studies have shown that scorpion venoms and toxins can decrease cancer growth, induce apoptosis and inhibit cancer progression and metastasis in vitro and in vivo. Several active molecules with anticancer activities, ranging from inhibition of proliferation and cell cycle arrest to induction of apoptosis and decreasing cell migration and invasion, have been isolated from scorpion venoms. These observations have shed light on the application of scorpion venoms and toxins as potential novel cancer therapeutics. This mini-review focuses on the anticancer potential of scorpion venoms and toxins and the possible mechanisms for their antitumor activities.

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JMJD6, a jumonji C (Jmj C) domain-containing protein demethylase and hydroxylase, has been implicated in an array of biological processes. It has been shown that JMJD6 interacts with and hydroxylates multiple serine/arginine-rich (SR) proteins and SR related proteins, including U2AF65, all of which are known to function in alternative splicing regulation. However, whether JMJD6 is widely involved in alternative splicing and the molecular mechanism underlying JMJD6-regulated alternative splicing have remained incompletely understood. Here, by using RASL-Seq, we investigated the functional impact of RNA-dependent interaction between JMJD6 and U2AF65, revealing that JMJD6 and U2AF65 co-regulated a large number of alternative splicing events. We further demonstrated the JMJD6 function in alternative splicing in jmjd6 knockout mice. Mechanistically, we showed that the enzymatic activity of JMJD6 was required for a subset of JMJD6-regulated splicing, and JMJD6-mediated lysine hydroxylation of U2AF65 could account for, at least partially, their co-regulated alternative splicing events, suggesting both JMJD6 enzymatic activity-dependent and independent control of alternative splicing. These findings reveal an intimate link between JMJD6 and U2AF65 in alternative splicing regulation, which has important implications in development and disease processes.

Objectives. Triple-negative breast cancer (TNBC) is well known for its strong invasiveness, rapid recurrence and poor prognosis.

Yin Yang 1 (YY1) is a multifunctional DNA-binding transcription factor shown to be critical in a variety of biological processes, and its activity and function have been shown to be regulated by multitude of mechanisms, which include but are not limited to post-translational modifications (PTMs), its associated proteins and cellular localization. YY2, the paralog of YY1 in mouse and human, has been proposed to function redundantly or oppositely in a context-specific manner compared with YY1. Despite its functional importance, how YY2’s DNA-binding activity and function are regulated, particularly by PTMs, remains completely unknown. Here we report the first PTM with functional characterization on YY2, namely lysine 247 monomethylation (K247me1), which was found to be dynamically regulated by SET7/9 and LSD1 both in vitro and in cultured cells. Functional study revealed that SET7/9-mediated YY2 methylation regulated its DNA-binding activity in vitro and in association with chromatin examined by chromatin immunoprecipitation coupled with sequencing (ChIP-seq) in cultured cells. Knockout of YY2, SET7/9 or LSD1 by CRISPR (clustered, regularly interspaced, short palindromic repeats)/Cas9-mediated gene editing followed by RNA sequencing (RNA-seq) revealed that a subset of genes was positively regulated by YY2 and SET7/9, but negatively regulated by LSD1, which were enriched with genes involved in cell proliferation regulation. Importantly, YY2-regulated gene transcription, cell proliferation and tumor growth were dependent, at least partially, on YY2 K247 methylation. Finally, somatic mutations on YY2 found in cancer, which are in close proximity to K247, altered its methylation, DNA-binding activity and gene transcription it controls. Our findings revealed the first PTM with functional implications imposed on YY2 protein, and linked YY2 methylation with its biological functions.