MYC‐binding lncRNA EPIC1 promotes AKT‐mTORC1 signaling and rapamycin resistance in breast and ovarian cancer

Abstract

AKT‐mTORC1 (mammalian target of rapamycin complex 1) signaling pathway plays a critical role in tumorigenesis and can be targeted by rapamycin. However, the underlying mechanism of how long noncoding RNA (lncRNAs) regulate the AKT‐mTORC1 pathway remains unclear. EPIC1 (epigenetically‐induced lncRNA 1) is a Myc‐binding lncRNA, which has been previously demonstrated to be overexpressed in multiple cancer types. In a pathway analysis including 4962 cancer patients, we observed that lncRNA EPIC1 expression was positively correlated with the AKT‐mTORC1 signaling pathway in more than 10 cancer types, including breast and ovarian cancers. RNA‐seq analysis of breast and ovarian cancer cells demonstrated that EPIC1‐knockdown led to the downregulation of genes in the AKT‐mTORC1 signaling pathway. In MCF‐7, OVCAR4, and A2780cis cell lines, EPIC1 knockdown and overexpression, respectively, inhibited and activated phosphorylated AKT and the downstream phosphorylation levels of 4EBP1 and S6K. Further knockdown of Myc abolished the EPIC1′s regulation of AKT‐mTORC1 signaling; suggested that the regulation of phosphorylation level of AKT, 4EBP1, and S6K by EPIC1 depended on the expression of Myc. Moreover, EPIC1 overexpressed MCF‐7, A2780cis, and OVCAR4 cells treated with rapamycin showed a significant decreasing in rapamycin mediated inhibition of p‐S6K and p‐S6 comparing with the control group. In addition, Colony Formation assay and MTT assay indicated that EPIC1 overexpression led to rapamycin resistance in breast and ovarian cancer cell lines. Our results demonstrated the lncRNA EPIC1 expression activated the AKT‐mTORC1 signaling pathway through Myc and led to rapamycin resistance in breast and ovarian cancer.

Long noncoding RNAs as therapeutic targets to overcome chemoresistance in ovarian cancer

“…Depletion of TMPO-AS1 suppressed the EMT and motility and 5-FU resistance in ovarian cancer cells ( Li et al, 2020b ). LncRNA EPIC1 enhanced rapamycin resistance via activation of AKT-mTORC1 pathway in ovarian cancer ( Wang et al, 2020b ). Myc was involved in EPIC1-mediated oncogenesis in ovarian cancer cells.…”

“…Myc was involved in EPIC1-mediated oncogenesis in ovarian cancer cells. Overexpression of lncRNA EPIC1 activated the AKT-mTORC1 pathway via Myc and caused rapamycin resistance in ovarian cancer ( Wang et al, 2020b ).…”

New progress of glutamine metabolism in the occurrence, development, and treatment of ovarian cancer from mechanism to clinic

“…One of its forms, mTORC1, transfers extracellular Gln into cells in the absence of amino acids (13). In ovarian cancer cells, mTORC1 is closely associated with Gln metabolism, and the mTORC1 signaling pathway is inhibited if the expression of the glutamine transporter is silenced (14). Pusapati et al found that combined inhibition of glycolysis and mTORC1 signaling disrupts metabolic reprogramming in ovarian cancer cells and inhibits their growth in vitro and in vivo (15).…”

“…One of its forms, mTORC1, transfers extracellular Gln into cells in the absence of amino acids ( 13 ). In ovarian cancer cells, mTORC1 is closely associated with Gln metabolism, and the mTORC1 signaling pathway is inhibited if the expression of the glutamine transporter is silenced ( 14 ). Pusapati et al.…”

The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer

“…The mTOR-specific inhibitor rapamycin is used for the therapy of some types of cancer, but cases of resistance to this drug have been described [ 264 ]. EPIC1 knockdown makes resistant breast and ovarian cancer cells sensitive to rapamycin [ 252 ]. High expression of EPIC1 lncRNA accelerates proliferation of lung cancer cells [ 243 ] and cholangiocarcinoma cells [ 224 ] and enhances invasive growth of colon cancer cells [ 229 ].…”