journal article·2025-05Open access

The Super Enhancer‐Driven Long Noncoding RNA PRKCQ‐AS1 Promotes Neuroblastoma Tumorigenesis by Interacting With MSI2 Protein and Is Targetable by Small Molecule Compounds

Sujanna Mondal, Pei Y. Liu, Janith Seneviratne, Antoine De Weck, Pooja Venkat, Chelsea Mayoh, Jing Wu, Jesper Maag, Jingwei Chen, Matthew Wong, Nenad Bartonicek, Poh Khoo, Lei Jin, Louise E. Ludlow, David S. Ziegler, Toby Trahair, Pieter Mestdagh, Belamy B. Cheung, Jinyan Li, Marcel E. Dinger, Ian Street, Xu D. Zhang, Glenn M. Marshall, Tao Liu

Advanced Science· Volume 12· Issue 18

Abstract

Abstract Tumorigenic drivers of MYCN gene nonamplified neuroblastoma remain largely uncharacterized. Long noncoding RNAs (lncRNAs) regulate tumorigenesis, however, there is little literature on therapeutic targeting of lncRNAs with small molecule compounds. Here PRKCQ‐AS1 is identified as the lncRNA most overexpressed in MYCN nonamplified, compared with MYCN‐amplified, neuroblastoma cell lines. PRKCQ‐AS1 expression is controlled by super‐enhancers, and PRKCQ‐AS1 RNA bound to MSI2 protein. RNA immunoprecipitation and sequencing identified BMX mRNA as the transcript most significantly disrupted from binding to MSI2 protein, after PRKCQ‐AS1 knockdown. PRKCQ‐AS1 or MSI2 knockdown reduces, while its overexpression enhances, BMX mRNA stability and expression, ERK protein phosphorylation and MYCN nonamplified neuroblastoma cell proliferation. PRKCQ‐AS1 knockdown significantly suppresses neuroblastoma progression in mice. In human neuroblastoma tissues, high levels of PRKCQ‐AS1 and MSI2 expression correlate with poor patient outcomes, independent of current prognostic markers. AlphaScreen of a compound library identifies NSC617570 as an efficient inhibitor of PRKCQ‐AS1 RNA and MSI2 protein interaction, and NSC617570 reduces BMX expression, ERK protein phosphorylation, neuroblastoma cell proliferation in vitro and tumor progression in mice. The study demonstrates that PRKCQ‐AS1 RNA interacts with MSI2 protein to induce neuroblastoma tumorigenesis, and that targeting PRKCQ‐AS1 and MSI2 interaction with small molecule compounds is an effective anticancer strategy.
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Research context

OpenAlex topics: Neuroblastoma Research and Treatments · interferon and immune responses · Cancer-related molecular mechanisms research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Children's Cancer Institute Australia and UNSW Centre for Childhood Cancer Research University of New South Wales Sydney NSW 2052 Australia

Garvan Institute of Medical Research Genome Informatics Genomics & Epigenetics Division, 384 Victoria St. Darlinghurst NSW 2010 Australia

School of Medicine and Public Health University of Newcastle Callaghan NSW 2308 Australia

Translational Research Institute Henan Provincial People's Hospital Tianjian Laboratory of Advanced Biomedical Science Academy of Medical Sciences Zhengzhou University Zhengzhou China

Murdoch Children's Research Institute The Royal Children's Hospital & Department of Paediatrics University of Melbourne Melbourne Australia

Kids Cancer Centre Sydney Children's Hospital High Street Randwick NSW 2031 Australia

Center for Medical Genetics Ghent Ghent University Ghent Belgium

Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen China

School of Life and Environmental Sciences Faculty of Science The University of Sydney Sydney NSW Australia

School of Clinical Medicine UNSW Medicine & Health UNSW Sydney Kensington NSW Australia

School of Medicine and Public Health Priority Research Centre for Cancer Research University of Newcastle Callaghan NSW 2308 Australia

Funding

National Health and Medical Research Council · U.S. Department of Defense

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