A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability.
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 progres...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-11-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1007802 |
| _version_ | 1819032675052158976 |
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| author | 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 G Prasanth Jian Ma Kannanganattu V Prasanth |
| author_facet | 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 G Prasanth Jian Ma Kannanganattu V Prasanth |
| author_sort | Mahdieh Jadaliha |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T07:05:42Z |
| format | Article |
| id | doaj.art-a0328846c8c04517aa1e82a87eb95ca4 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-21T07:05:42Z |
| publishDate | 2018-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-a0328846c8c04517aa1e82a87eb95ca42022-12-21T19:12:07ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042018-11-011411e100780210.1371/journal.pgen.1007802A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability.Mahdieh JadalihaOmid GholamalamdariWei TangYang ZhangAna PetracoviciQinyu HaoAamira TariqTae Gyoon KimSarah E HoltonDeepak K SinghXiao Ling LiSusan M FreierStefan AmbsRohit BhargavaAshish LalSupriya G PrasanthJian MaKannanganattu V PrasanthThe 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.https://doi.org/10.1371/journal.pgen.1007802 |
| spellingShingle | 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 G Prasanth Jian Ma Kannanganattu V Prasanth A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability. PLoS Genetics |
| title | A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability. |
| title_full | A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability. |
| title_fullStr | A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability. |
| title_full_unstemmed | A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability. |
| title_short | A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability. |
| title_sort | natural antisense lncrna controls breast cancer progression by promoting tumor suppressor gene mrna stability |
| url | https://doi.org/10.1371/journal.pgen.1007802 |
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