ORCID Profile
0000-0001-7261-1423
Current Organisations
Monash University
,
University of Oxford
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Publisher: Proceedings of the National Academy of Sciences
Date: 14-06-2016
Abstract: The plasticity of Polycomb repressive complex 2 (PRC2) in the context of tumorigenesis has remained a subject of contention. Here we demonstrate that the equilibrium between the oncogenic and tumor-suppressive activity of PRC2 in promoting breast cancer invasion is tightly regulated by hypoxia-inducible factor 1-α. PRC2 acts as a tumor-suppressor barrier to the hypoxia-driven invasion pathway, and the impaired PRC2 activity upon hypoxia promotes a chromatin switch at proinvasion matrix metalloproteinase gene loci. The study fundamentally changed our understanding of the role of PRC2 in breast cancer and also identified a previously unidentified function of enhancer of zeste 2 to complex with Forkhead box M1 to promote cancer invasion.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2012
Abstract: Resistance to tyrosine kinase inhibitors (TKIs) remains a challenge in management of patients with chronic myeloid leukemia (CML). A better understanding of the BCR-ABL signalling network may lead to better therapy. Here we report the discovery of a novel downstream target of BCR-ABL signalling, PRL-3 ( PTP4A3 ), an oncogenic tyrosine phosphatase. Analysis of CML cancer cell lines and CML patient s les reveals the upregulation of PRL-3. Inhibition of BCR-ABL signalling either by Imatinib or by RNAi silencing BCR-ABL reduces PRL-3 and increases cleavage of PARP. In contrast, the amount of PRL-3 protein remains constant or even increased in response to Imatinib treatment in drug resistant cells expressing P210 T315I. Finally, analysis with specific shRNA shows PRL-3 involvement in the proliferation and self-renewal of CML cells. These data support a role for PRL-3 in BCR-ABL signalling and CML biology and may be a potential therapeutic target downstream of BCR-ABL in TKI resistant mutant cells.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-05-2021
Abstract: Genome-scale CRISPR screen identifies KMT2A as a druggable target against Wnt/β-catenin signaling and colorectal cancer.
Publisher: Public Library of Science (PLoS)
Date: 12-05-2011
Publisher: Informa UK Limited
Date: 15-08-2016
Publisher: American Society of Hematology
Date: 08-09-2011
DOI: 10.1182/BLOOD-2010-07-294827
Abstract: Recent studies have shown that 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, disrupts polycomb-repressive complex 2 (PRC2), and preferentially induces apoptosis in cancer cells, including acute myeloid leukemia (AML). However, the underlying molecular mechanisms are not well understood. The present study demonstrates that DZNep induces robust apoptosis in AML cell lines, primary cells, and targets CD34+CD38− leukemia stem cell (LSC)–enriched subpopulations. Using RNA interference (RNAi), gene expression profiling, and ChIP, we identified that TXNIP, a major redox control molecule, plays a crucial role in DZNep-induced apoptosis. We show that disruption of PRC2, either by DZNep treatment or EZH2 knockdown, reactivates TXNIP, inhibits thioredoxin activity, and increases reactive oxygen species (ROS), leading to apoptosis. Furthermore, we show that TXNIP is down-regulated in AML and is a direct target of PRC2-mediated gene silencing. Consistent with the ROS accumulation on DZNep treatment, we also see a signature of endoplasmic reticulum (ER) stress-regulated genes, commonly associated with cell survival, down-regulated by DZNep. Taken together, we uncover a novel molecular mechanism of DZNep-mediated apoptosis and propose that EZH2 may be a potential new target for epigenetic treatment in AML.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.MOLCEL.2021.11.015
Abstract: Mediator kinases (CDK8/19) are transcriptional regulators broadly implicated in cancer. Despite their central role in fine-tuning gene-expression programs, we find complete loss of CDK8/19 is tolerated in colorectal cancer (CRC) cells. Using orthogonal functional genomic and pharmacological screens, we identify BET protein inhibition as a distinct vulnerability in CDK8/19-depleted cells. Combined CDK8/19 and BET inhibition led to synergistic growth retardation in human and mouse models of CRC. Strikingly, depletion of CDK8/19 in these cells led to global repression of RNA polymerase II (Pol II) promoter occupancy and transcription. Concurrently, loss of Mediator kinase led to a profound increase in MED12 and BRD4 co-occupancy at enhancer elements and increased dependence on BET proteins for the transcriptional output of cell-essential genes. In total, this work demonstrates a synthetic lethal interaction between Mediator kinase and BET proteins and exposes a therapeutic vulnerability that can be targeted using combination therapies.
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2015
End Date: 2016
Funder: Congressionally Directed Medical Research Programs
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