TY - JOUR
T1 - Sabotaging of the oxidative stress response by an oncogenic noncoding RNA
AU - Mahajan, Nitin
AU - Wu, Hua Jun
AU - Bennett, Richard L.
AU - Troche, Catalina
AU - Licht, Jonathan D.
AU - Weber, Jason D.
AU - Maggi, Leonard B.
AU - Tomasson, Michael H.
N1 - Funding Information:
This work was supported, in part, by the U.S. National Institutes of Health, National Cancer Institute (Grants R01- CA174743 to M.H.T. and L.B.M., and R01-CA-175349 to M.H.T.). The authors thank M. Bates (University of Iowa, Iowa City, IA, USA) for her critical review. The authors also thank all the members of the M.H.T. laboratory for discussion and suggestions, and the Genome Technology Access Center (Department of Genetics, Washington University School of Medicine) for help with genomic analysis.
Publisher Copyright:
© FASEB.
PY - 2017/2
Y1 - 2017/2
N2 - Overexpression of the multiplemyeloma 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, includingmultiplemyeloma (MM).ACA11 andMMSETare overexpressedcotranscriptionally 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 -negativeMMpatient bone marrow samples revealed an enhanced oxidative phosphorylationmRNAsignature. Supporting these data,ACA11 overexpression in a t(4;14)-negativeMMcell line, MM1.S, demonstrated enhanced reactive oxygen species (ROS) levels. In addition, an enhancement of cell proliferation, increased soft agar colony size, and elevatedERK1/2phosphorylationwere observed.ThisACA11-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. FASEB J. 31, 482-490 (2017). www.fasebj.org.
AB - Overexpression of the multiplemyeloma 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, includingmultiplemyeloma (MM).ACA11 andMMSETare overexpressedcotranscriptionally 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 -negativeMMpatient bone marrow samples revealed an enhanced oxidative phosphorylationmRNAsignature. Supporting these data,ACA11 overexpression in a t(4;14)-negativeMMcell line, MM1.S, demonstrated enhanced reactive oxygen species (ROS) levels. In addition, an enhancement of cell proliferation, increased soft agar colony size, and elevatedERK1/2phosphorylationwere observed.ThisACA11-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. FASEB J. 31, 482-490 (2017). www.fasebj.org.
KW - ACA11
KW - Multiple myeloma
KW - NRF2
KW - ROS
KW - snoRNA
UR - http://www.scopus.com/inward/record.url?scp=85011301026&partnerID=8YFLogxK
U2 - 10.1096/fj.201600654R
DO - 10.1096/fj.201600654R
M3 - Article
C2 - 28148777
AN - SCOPUS:85011301026
SN - 0892-6638
VL - 31
SP - 482
EP - 490
JO - FASEB Journal
JF - FASEB Journal
IS - 2
ER -