A nuclear lncRNA Linc00839 as a Myc target to promote breast cancer chemoresistance via PI3K/AKT signaling pathway

Abstract

Chemoresistance has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Long noncoding RNAs play important roles in breast cancer tumorigenesis and chemoresistance. However, the involvement and regulation of lncRNAs in breast cancer chemoresistance are not completely understood. Here, we reported that Linc00839 was localized in the nucleus and upregulated in chemoresistant breast cancer cells and tissues, and high level of Linc00839 was associated with a poor prognosis. Knockdown of Linc00839 significantly suppressed proliferation, invasion, and migration, sensitized cells to paclitaxel in vitro and inhibited transplant tumor development in vivo. Mechanistically, we found that Myc could directly bind to the promoter region of Linc00839 and activate its transcription. Furthermore, Linc00839 overexpression increased the expression of Myc and the RNA‐binding protein Lin28B and activated the PI3K/AKT signaling pathway. We also discovered that Lin28B positively interacted with Linc00839 and was upregulated in breast cancer tissues. Taken together, for the first time, we showed that Linc00839 was activated by Myc and promoted proliferation and chemoresistance in breast cancer through binding with Lin28B. These findings provide new insight into the regulatory mechanism of Linc00839 and propose a Myc/Linc00839/Lin28B feedback loop that could be used as a novel therapeutic target for breast cancer.

Small in Size, but Large in Action: microRNAs as Potential Modulators of PTEN in Breast and Lung Cancers

“…CTD decreases the expression of miRNA-160b-93 as a tumor-promoting factor to enhance the expression of its downstream target PTEN, resulting in breast cancer inhibition [ 306 ]. Matrine is also an alkaloid derived from Sophora flavescens with capability in regulating the expression of miRNAs in cancer therapy [ 307 ]. It is noteworthy that it has been reported that matrine can regulate the miRNA/PTEN axis in colorectal cancer therapy [ 231 ], which is the same strategy that is followed in breast cancer therapy.…”

An Overview of Long Non-Coding (lnc)RNAs in Neuroblastoma

“…Long intergenic non-protein coding RNA 839 (LINC00839) was also studied in breast cancer [100] and osteosarcoma [101]. Its upregulation correlated with bad prognosis in both cases.…”

“…Its upregulation correlated with bad prognosis in both cases. In particular, Chen et al [100] described the mechanism by which this lncRNA acts in breast cancer cells: it is transcriptionally activated by MYC interaction with its promoter and can bind Lin28b, promoting positive regulation of both MYC and Lin28b protein. Despite this mechanism occurring in breast cancer cells, it is interesting to note that LIN28B overexpression promotes NB onset [102].…”

Epigenetic Mechanisms of LncRNAs Binding to Protein in Carcinogenesis

“…In breast cancers, it is reported that lncRNA BORG enhances chemo-resistant traits by binding to RPA1, which stimulates the NF-κB signaling pathway in triple-negative breast cancer [ 119 ]. Binding of LINC00839 with Lin28B impairs chemotherapeutic outcomes via the PI3K/AKT signaling pathway in breast cancer [ 120 ]. LncRNA GBCDRlnc1 binds to PGK1 and prevents its degradation to subsequently activate its downstream targets, such as ATG5-ATG12, that can induce autophagy and chemoresistance in gallbladder cancer [ 121 ].…”