A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability.

Autor: Jadaliha M; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Gholamalamdari O; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Tang W; Laboratory of human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America., Zhang Y; Department of Bioengineering and Beckman Institute of Advanced Science and Technology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Petracovici A; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Hao Q; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Tariq A; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Kim TG; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Holton SE; Department of Bioengineering and Beckman Institute of Advanced Science and Technology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Singh DK; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Li XL; Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America., Freier SM; Ionis Pharmaceuticals Inc., Carlsbad, CA, United States of America., Ambs S; Laboratory of human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America., Bhargava R; Department of Bioengineering and Beckman Institute of Advanced Science and Technology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Lal A; Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America., Prasanth SG; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America., Ma J; Department of Bioengineering and Beckman Institute of Advanced Science and Technology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America.; School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, United States of America., Prasanth KV; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2018 Nov 29; Vol. 14 (11), pp. e1007802. Date of Electronic Publication: 2018 Nov 29 (Print Publication: 2018).
DOI: 10.1371/journal.pgen.1007802
Abstrakt: The human genome encodes thousands of long noncoding RNA (lncRNA) genes; the function of majority of them is poorly understood. Aberrant expression of a significant number of lncRNAs is observed in various diseases, including cancer. To gain insights into the role of lncRNAs in breast cancer progression, we performed genome-wide transcriptome analyses in an isogenic, triple negative breast cancer (TNBC/basal-like) progression cell lines using a 3D cell culture model. We identified significantly altered expression of 1853 lncRNAs, including ~500 natural antisense transcript (NATs) lncRNAs. A significant number of breast cancer-deregulated NATs displayed co-regulated expression with oncogenic and tumor suppressor protein-coding genes in cis. Further studies on one such NAT, PDCD4-AS1 lncRNA reveal that it positively regulates the expression and activity of the tumor suppressor PDCD4 in mammary epithelial cells. Both PDCD4-AS1 and PDCD4 show reduced expression in TNBC cell lines and in patients, and depletion of PDCD4-AS1 compromised the cellular levels and activity of PDCD4. Further, tumorigenic properties of PDCD4-AS1-depleted TNBC cells were rescued by exogenous expression of PDCD4, implying that PDCD4-AS1 acts upstream of PDCD4. Mechanistically, PDCD4-AS1 stabilizes PDCD4 RNA by forming RNA duplex and controls the interaction between PDCD4 RNA and RNA decay promoting factors such as HuR. Our studies demonstrate crucial roles played by NAT lncRNAs in regulating post-transcriptional gene expression of key oncogenic or tumor suppressor genes, thereby contributing to TNBC progression.
Competing Interests: SMF is an employee of Ionis Inc. and receives salary from Ionis Inc. The other authors have declared that no competing interests exist.
Databáze: MEDLINE
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