Sabotaging of the oxidative stress response by an oncogenic noncoding RNA.
Overexpression of the multiple myeloma set domain (MMSET) Wolf-Hirschhorn syndrome candidate 1 gene, which contains an orphan box H/ACA class small nucleolar RNA, ACA11, in an intron, is associated with several cancer types, including multiple myeloma (MM). ACA11 and MMSET are overexpressed cotranscriptionally as a result of the t(4;14) chromosomal translocation in a subset of patients with MM. RNA sequencing of CD138+tumor cells from t(4;14)-positive and -negative MM patient bone marrow samples revealed an enhanced oxidative phosphorylation mRNA signature. Supporting these data, ACA11 overexpression in a t(4;14)-negative MM cell line, MM1.S, demonstrated enhanced reactive oxygen species (ROS) levels. In addition, an enhancement of cell proliferation, increased soft agar colony size, and elevated ERK1/2 phosphorylation were observed. This ACA11-driven hyperproliferative phenotype depended on increased ROS levels as exogenously added antioxidants attenuate the increased proliferation. A major transcriptional regulator of the cellular antioxidant response, nuclear factor (erythroid-derived 2)-like 2 (NRF2), shuttled to the nucleus, as expected, in response to ACA11-driven increases in ROS; however, transcriptional up-regulation of some of NRF2's antioxidant target genes was abrogated in the presence of ACA11 overexpression. These data show for the first time that ACA11 promotes proliferation through inhibition of NRF2 function resulting in sustained ROS levels driving cancer cell proliferation.-Mahajan, N., Wu, H.-J., Bennett, R. L., Troche, C., Licht, J. D., Weber, J. D., Maggi, L. B., Jr., Tomasson, M. H. Sabotaging of the oxidative stress response by an oncogenic noncoding RNA.
Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.
Nitin
N
Mahajan
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; and.
Hua-Jun
HJ
Wu
Division of Hematology and Oncology, Department of Medicine, University of Florida Health Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, USA.
Richard L
RL
Bennett
Division of Hematology and Oncology, Department of Medicine, University of Florida Health Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, USA.
Catalina
C
Troche
Division of Hematology and Oncology, Department of Medicine, University of Florida Health Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, USA.
Jonathan D
JD
Licht
Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.
Jason D
JD
Weber
Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA; lmaggi@dom.wustl.edu.
Leonard B
LB
Maggi
Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA; tomasson@dom.wustl.edu.
Michael H
MH
Tomasson
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes / Q000502:physiology*; D018384:Oxidative Stress; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D022661:RNA, Untranslated; D017382:Reactive Oxygen Species
ACA11; NRF2; ROS; multiple myeloma; snoRNA