Journal article
Sabotaging of the oxidative stress response by an oncogenic noncoding RNA
The FASEB journal, Vol.31(2), pp.482-490
02/01/2017
DOI: 10.1096/fj.201600654R
PMCID: PMC5240659
PMID: 28148777
Abstract
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 -negativeMMpatient 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.
Details
- Title: Subtitle
- Sabotaging of the oxidative stress response by an oncogenic noncoding RNA
- Creators
- Nitin Mahajan - Washington University in St. LouisHua-Jun Wu - Dana-Farber Cancer InstituteRichard L. Bennett - University of Florida HealthCatalina Troche - University of Florida HealthJonathan D. Licht - University of Florida HealthJason D. Weber - Washington University in St. LouisLeonard B. Maggi - Washington University in St. LouisMichael H. Tomasson - Washington University in St. Louis School of Medicine
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.31(2), pp.482-490
- DOI
- 10.1096/fj.201600654R
- PMID
- 28148777
- PMCID
- PMC5240659
- NLM abbreviation
- FASEB J
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Publisher
- Federation Amer Soc Exp Biol
- Number of pages
- 9
- Grant note
- P30CA091842 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01-CA174743; R01-CA-175349 / U.S. National Institutes of Health, National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 02/01/2017
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984359675302771
Metrics
12 Record Views