Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer

Machitani, Mitsuhiro; Sakurai, Fuminori; Wakabayashi, Keisaku; Tachibana, Masashi; Fujiwara, Toshiyoshi; Mizuguchi, Hiroyuki

doi:10.1158/1535-7163.mct-16-0383

Cited by 19 publications

(20 citation statements)

References 36 publications

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“…Finally, how LAMP5 might be suppressed in a therapeutic setting should also be considered for further translational application. Based on recent progress in oncolytic viruses (47)(48)(49)(50), using an adenovirusmediated short hairpin RNA delivery system containing shRNA targeting LAMP5 or CRISPR-Cas9 containing sgRNA targeting LAMP5 may be an alternative method for suppressing LAMP5 in future clinical application.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia

Wang

Han

Sun

et al. 2019

Clinical Cancer Research

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Purpose: Despite many attempts to understand mixedlineage leukemia (MLL leukemia), effective therapies for this disease remain limited. We identified a lysosome-associated membrane protein (LAMP) family member, LAMP5, that is specifically and highly expressed in patients with MLL leukemia. The purpose of the study was to demonstrate the functional relevance and clinical value of LAMP5 in the disease. Experimental Design: We first recruited a large cohort of leukemia patients to validate LAMP5 expression and evaluate its clinical value. We then performed in vitro and in vivo experiments to investigate the functional relevance of LAMP5 in MLL leukemia progression or maintenance. Results: LAMP5 was validated as being specifically and highly expressed in patients with MLL leukemia and was associated with a poor outcome. Functional studies showed that LAMP5 is a novel autophagic suppressor and protects MLL fusion proteins from autophagic degradation. Specifically targeting LAMP5 significantly promoted degradation of MLL fusion proteins and inhibited MLL leukemia progression in both an animal model and primary cells. We further revealed that LAMP5 is a direct target of the H3K79 histone methyltransferase DOT1L. Downregulating LAMP5 with a DOT1L inhibitor enhanced the selective autophagic degradation of MLL oncoproteins and extended survival in vivo; this observation was especially significant when combining DOT1L inhibitors with LAMP5 knockdown. Conclusions: This study demonstrates that LAMP5 serves as a "bodyguard" for MLL fusions to evade degradation and is the first to link H3K79 methylation to autophagy regulation, highlighting the potential of LAMP5 as a therapeutic target for MLL leukemia.

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Section: Discussionmentioning

confidence: 99%

Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia

Wang

Han

Sun

et al. 2019

Clinical Cancer Research

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“…The aim of this study was to examine whether Ad infection is regulated by miRNA-mediated posttranscriptional silencing and to identify miRNAs and their target genes involved in Ad infection. Our previous studies demonstrated that Dicer-mediated cleavage of Ad-encoded small noncoding RNAs (VA-RNAs) negatively regulated Ad replication and that Dicer knockdown led to the promotion of Ad replication (28,44). In addition, knockdown of Ago2, which is a major component of the RISC, also promoted Ad replication, although the HeLa cells were pretreated with PD0332991 at 1 M, followed by infection with WT-Ad at 100 VP/cell.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA miR-27 Inhibits Adenovirus Infection by Suppressing the Expression of SNAP25 and TXN2

Machitani

Sakurai

Wakabayashi

et al. 2017

J Virol

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Recent studies have reported that host microRNAs (miRNAs) regulate infections by several types of viruses via various mechanisms and that inhibition of the miRNA processing factors enhances or prevents viral infection. However, it has not been clarified whether these effects of miRNAs extend to adenovirus (Ad) infection. Here we show that miR-27a and -b efficiently inhibit infection with an Ad via the downregulation of SNAP25 and TXN2, which are members of the SNARE proteins and the thioredoxin family, respectively. Approximately 80% reductions in Ad genomic copy number were found in cells transfected with miR-27a/b mimics, whereas there were approximately 2.5-to 5-fold larger copy numbers of the Ad genome following transfection with miR-27a/b inhibitors. Microarray gene expression analysis and in silico analysis demonstrated that SNAP25 and TXN2 are target genes of miR-27a/b. A reporter assay using plasmids containing the 3= untranslated regions of the SNAP25 and TXN2 genes showed that miR-27a/b directly suppressed SNAP25 and TXN2 expression through posttranscriptional gene silencing. Knockdown of SNAP25 led to a significant inhibition of Ad entry into cells. Knockdown of TXN2 induced cell cycle arrest at G 1 phase, leading to a reduction in Ad replication. In addition, overexpression of Ad-encoded small noncoding RNAs (VA-RNAs) restored the miR-27a/b-mediated reduction in infection level with a VA-RNA-lacking Ad mutant due to the VA-RNA-mediated inhibition of miR-27a/b expression. These results indicate that miR-27a and -b suppress SNAP25 and TXN2 expression via posttranscriptional gene silencing, leading to efficient suppression of Ad infection.IMPORTANCE Adenovirus (Ad) is widely used as a platform for replication-incompetent Ad vectors (Adv) and replication-competent oncolytic Ad (OAd) in gene therapy and virotherapy. Regulation of Ad infection is highly important for efficient gene therapies using both Adv and OAd. In this study, we demonstrate that miR-27a and -b, which are widely expressed in host cells, suppress SNAP25 and TXN2 expression through posttranscriptional gene silencing. Suppression of SNAP25 and TXN2 expression leads to inhibition of Ad entry into cells and to cell cycle arrest, respectively, leading to efficient suppression of Ad infection. Our findings provide important clues to the improvement of gene therapies using both Adv and OAd.KEYWORDS SNAP25, TXN2, adenoviruses, miR-27, posttranscriptional gene silencing

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“…It is also possible to improve oncolytic Ad by incorporation of a short-hairpin RNA which functions to downregulate Dicer (an endoribonuclease which has a role in processing virus-associated RNA). Downregulation of this protein inhibits the destruction of viral RNA and allows Ad to replicate efficiently and therefore improves the efficacy of this OV ( 54 ).…”

Section: Adenovirusmentioning

confidence: 99%

Oncolytic Viruses—Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer

et al. 2017

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Oncolytic viruses (OVs) are an emerging treatment option for many cancer types and have recently been the focus of extensive research aiming to develop their therapeutic potential. The ultimate aim is to design a virus which can effectively replicate within the host, specifically target and lyse tumor cells and induce robust, long lasting tumor-specific immunity. There are a number of viruses which are either naturally tumor-selective or can be modified to specifically target and eliminate tumor cells. This means they are able to infect only tumor cells and healthy tissue remains unharmed. This specificity is imperative in order to reduce the side effects of oncolytic virotherapy. These viruses can also be modified by various methods including insertion and deletion of specific genes with the aim of improving their efficacy and safety profiles. In this review, we have provided an overview of the various virus species currently being investigated for their oncolytic potential and the positive and negative effects of a multitude of modifications used to increase their infectivity, anti-tumor immunity, and treatment safety, in particular focusing on the interaction of tumor cells and OVs.

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Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer

Cited by 19 publications

References 36 publications

Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia

Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia

MicroRNA miR-27 Inhibits Adenovirus Infection by Suppressing the Expression of SNAP25 and TXN2

Oncolytic Viruses—Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer

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