A single N6-methyladenosine site regulates lncRNA HOTAIR function in breast cancer cells.
Allison M PormanJustin T RobertsEmily D DuncanMadeline L ChrupcalaAriel A LevineMichelle A KennedyMichelle M WilliamsJennifer K RicherAaron M JohnsonPublished in: PLoS biology (2022)
N6-methyladenosine (m6A) modification of RNA regulates normal and cancer biology, but knowledge of its function on long noncoding RNAs (lncRNAs) remains limited. Here, we reveal that m6A regulates the breast cancer-associated human lncRNA HOTAIR. Mapping m6A in breast cancer cell lines, we identify multiple m6A sites on HOTAIR, with 1 single consistently methylated site (A783) that is critical for HOTAIR-driven proliferation and invasion of triple-negative breast cancer (TNBC) cells. Methylated A783 interacts with the m6A "reader" YTHDC1, promoting chromatin association of HOTAIR, proliferation and invasion of TNBC cells, and gene repression. A783U mutant HOTAIR induces a unique antitumor gene expression profile and displays loss-of-function and antimorph behaviors by impairing and, in some cases, causing opposite gene expression changes induced by wild-type (WT) HOTAIR. Our work demonstrates how modification of 1 base in an lncRNA can elicit a distinct gene regulation mechanism and drive cancer-associated phenotypes.
Keyphrases
- gene expression
- induced apoptosis
- genome wide
- wild type
- cell cycle arrest
- endothelial cells
- dna methylation
- long non coding rna
- healthcare
- transcription factor
- long noncoding rna
- squamous cell carcinoma
- oxidative stress
- genome wide identification
- dna damage
- endoplasmic reticulum stress
- cell death
- mass spectrometry
- squamous cell
- pi k akt
- induced pluripotent stem cells