Sabotaging of the oxidative stress response by an oncogenic noncoding RNA

Abstract

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.