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

Mahdieh Jadaliha, Omid Gholamalamdari, Wei Tang, Yang Zhang, Ana Petracovici, Qinyu Hao, Aamira Tariq, Tae Gyoon Kim, Sarah E. Holton, Deepak K. Singh, Xiao Ling Li, Susan M. Freier, Stefan Ambs, Rohit Bhargava, Ashish Lal, Supriya Gangadharan Prasanth, Jian Ma, Prasanth Kumar Kannanganattu

Research output: Contribution to journalArticle

Abstract

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 compromise 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.

Original languageEnglish (US)
Article numbere1007802
JournalPLoS genetics
Volume14
Issue number11
DOIs
StatePublished - Nov 2018

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Long Noncoding RNA
tumor suppressor genes
RNA Stability
Tumor Suppressor Genes
tumor
breast neoplasms
RNA
cancer
Breast Neoplasms
gene
cell lines
neoplasms
genome
transcriptome
breasts
cell culture
epithelial cells
Triple Negative Breast Neoplasms
genes
Tumor Suppressor Proteins

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability. / Jadaliha, Mahdieh; Gholamalamdari, Omid; Tang, Wei; Zhang, Yang; Petracovici, Ana; Hao, Qinyu; Tariq, Aamira; Kim, Tae Gyoon; Holton, Sarah E.; Singh, Deepak K.; Li, Xiao Ling; Freier, Susan M.; Ambs, Stefan; Bhargava, Rohit; Lal, Ashish; Prasanth, Supriya Gangadharan; Ma, Jian; Kannanganattu, Prasanth Kumar.

In: PLoS genetics, Vol. 14, No. 11, e1007802, 11.2018.

Research output: Contribution to journalArticle

Jadaliha, M, Gholamalamdari, O, Tang, W, Zhang, Y, Petracovici, A, Hao, Q, Tariq, A, Kim, TG, Holton, SE, Singh, DK, Li, XL, Freier, SM, Ambs, S, Bhargava, R, Lal, A, Prasanth, SG, Ma, J & Kannanganattu, PK 2018, 'A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability', PLoS genetics, vol. 14, no. 11, e1007802. https://doi.org/10.1371/journal.pgen.1007802
Jadaliha, Mahdieh ; Gholamalamdari, Omid ; Tang, Wei ; Zhang, Yang ; Petracovici, Ana ; Hao, Qinyu ; Tariq, Aamira ; Kim, Tae Gyoon ; Holton, Sarah E. ; Singh, Deepak K. ; Li, Xiao Ling ; Freier, Susan M. ; Ambs, Stefan ; Bhargava, Rohit ; Lal, Ashish ; Prasanth, Supriya Gangadharan ; Ma, Jian ; Kannanganattu, Prasanth Kumar. / A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability. In: PLoS genetics. 2018 ; Vol. 14, No. 11.
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abstract = "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 compromise 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.",
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AU - Gholamalamdari, Omid

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AU - Petracovici, Ana

AU - Hao, Qinyu

AU - Tariq, Aamira

AU - Kim, Tae Gyoon

AU - Holton, Sarah E.

AU - Singh, Deepak K.

AU - Li, Xiao Ling

AU - Freier, Susan M.

AU - Ambs, Stefan

AU - Bhargava, Rohit

AU - Lal, Ashish

AU - Prasanth, Supriya Gangadharan

AU - Ma, Jian

AU - Kannanganattu, Prasanth Kumar

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