Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission.

Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of excessively asymmetric mitofission-associated cell death (MFAD) by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy. By screening a series of pan-inhibitors, we identified pracinostat, a pan-histone deacetylase (HDAC) inhibitor, as a novel MFAD inducer, that exhibited a significant anticancer effect on colorectal cancer (CRC) in vivo and in vitro. Pracinostat increased the expression of cyclin-dependent kinase 5 (CDK5) and induced its acetylation at residue lysine 33, accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynamin-related protein 1 (Drp1)-mediated mitochondrial peripheral fission. CRC cells with high level of CDK5 (CDK5-high) displayed midzone mitochondrial division that was associated with oncogenic phenotype, but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells. Mechanistically, pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor (MFF) to mitochondrial fission 1 protein (FIS1). Thus, our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.

Hsa-miR-335 enhances cell migration and invasion in lung adenocarcinoma through targeting Copine-1.

Lung adenocarcinoma (LAC) is one of the most common pulmonary adenocarcinomas with a high peak of mortality, and metastasis is the main culprit of LAC deaths. microRNAs play important role in cancer metastasis, and thus are regarded as potential diagnostic and prognostic markers for human cancers. However, many miRNAs exhibit dual roles in diverse cellular contexts. Here, we revealed that hsa-miR-335, a previously reported tumor suppressor, exhibited an oncogenic role in LAC. Overexpression of miR-335 enhanced the abilities of A549 and H1299 cells to invade and migrate by regulating epithelial-mesenchymal transition, while inhibition of miR-335 exhibited an opposite effect in vitro and in vivo. Mechanically, miR-335 inhibited the expression of Copine-1 (CPNE1), an NF-κB suppressor, through interacting with its mRNA 3'UTR, while mutating the binding sites abolished this inhibitory effect. This finding not only highlights the suppressive effect of CPNE1 on cell motility, but also provides new insight into miR-335 in promoting LAC metastasis.

Differential Expression Profiles and Functional Predication of Circular Ribonucleic Acid in Traumatic Spinal Cord Injury of Rats.

Recent studies indicate that circular ribonucleic acids (circRNAs) are involved in a variety of human diseases. The roles of circRNAs in traumatic spinal cord injury (SCI) remain unknown, however. We performed RNA-seq to analyze the circRNA expression profile in rat spinal cord after SCI and to investigate the relevant mechanisms. In all, 150 circRNAs were significantly differentially expressed in rat spinal cord after SCI by a fold-change ≥2 and p value ≤0.05. Among these, 99 circRNAs were upregulated, while 51 were downregulated. Gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway analyses, and circRNA/miocroRNA (miRNA) interaction networks were conducted to predict the potential roles of circRNAs in the process of SCI. In addition, the expression levels of six selected circRNAs were verified successfully by quantitative real-time polymerase chain reaction. Further study identified circRNA_07079 and circRNA_01282 as being associated with SCI, and they may participate in the pathophysiology of SCI through circRNA-targeted miRNA-messenger RNA axis. In summary, the results of our study revealed the expression profiles and potential functions of differentially expressed circRNAs in traumatic SCI in rats; this may provide new clues for studying the mechanisms underlying SCI and also present novel molecular targets for clinical therapy of SCI.

Silencing of circRNA.2837 Plays a Protective Role in Sciatic Nerve Injury by Sponging the miR-34 Family via Regulating Neuronal Autophagy.

Circular RNAs (circRNAs) represent a class of non-coding RNAs that are involved in transcriptional and posttranscriptional gene expression regulation and associated with different kinds of human diseases. However, the characterization and function of circular RNAs in peripheral nerve injuries remain elusive. Here, we established a rat sciatic nerve injury model and identified at least 4,942 distinct circular RNA candidates and a series of circular RNAs that were differentially expressed in injured nerve tissues compared with matched normal tissues. We characterized one frequently downregulated circular RNA, circRNA.2837, and further investigated its function in sciatic nerve injury. We found that circRNA.2837 regulated autophagy in neurons in vitro and in vivo, and downregulation of circRNA.2837 alleviated sciatic nerve injury via inducing autophagy in vivo. Mechanistically, knockdown of circRNA.2837 may protect neurons against neurological injury by acting as a sponge for members of miR-34 family. Our findings suggested that differentially expressed circular RNAs were involved in the pathogenesis of sciatic nerve injury, and circular RNAs exerted regulatory functions in sciatic nerve injury and might be used as potential targets in sciatic nerve injury therapy.