LncRNA H19 is a major mediator of doxorubicin chemoresistance in breast cancer cells through a cullin4A-MDR1 pathway

Abstract

Development of chemoresistance is a persistent problem during cancer treatment. Long non-coding RNAs (LncRNAs) are currently emerging as an integral functional component of the human genome and as critical regulators of cancer development and progression. In the present study, we investigated the role and molecular mechanism of H19 lncRNA in chemoresistance development by using doxorubicin (Dox) resistance in breast cancer cells as a model system. H19 lncRNA expression was significantly increased in anthracycline-treated and Dox-resistant MCF-7 breast cancer cells. This H19 overexpression was contributed to cancer cell resistance to anthracyclines and paclitaxel as knockdown of H19 lncRNA by a specific H19 shRNA in Dox-resistant cells significantly improved the cell sensitivity to anthracyclines and paclitaxel. Furthermore, gene expression profiling analysis revealed that a total of 192 genes were associated with H19-mediated Dox resistance. These genes were enriched in multiple KEGG pathways that are related to chemoresistance. Using genetic and pharmacological approaches, we demonstrated that MDR1 and MRP4 were major effectors of H19-regulated Dox resistance in breast cancer cells as MDR1 and MRP4 expression was markedly elevated in Dox-resistant cells while dramatically reduced when H19 was knocked down. Moreover, we found that CUL4A, an ubiquitin ligase component, was a critical factor bridging H19 lncRNA to MDR1 expression, and a high tumor CUL4A expression was associated with low survival in breast cancer patients treated with chemotherapy. These data suggest that H19 lncRNA plays a leading role in breast cancer chemoresistance, mediated mainly through a H19-CUL4A-ABCB1/MDR1 pathway.

Long non‑coding RNA SNHG1 promotes breast cancer progression by regulation of LMO4

“…Subsequent experimental analysis identified several lncRNAs which act as oncogenes or tumor suppressors in this type of cancer (38)(39)(40). Moreover, the overexpression or downregulation of lncRNAs has been used as a breast cancer biomarker, aiming to improve detection of this disease at an early stage or predict the sensitivity of the patients to chemotherapy (41)(42)(43). The present study demonstrated that lncRNA small nucleolar RNA host gene 1 (SNHG1) was overexpressed in breast cancer and that it promoted breast cancer cell growth, cell cycle and migration, suggesting its oncogenic role.…”

LncRNA FENDRR attenuates adriamycin resistance via suppressing MDR1 expression through sponging HuR and miR‐184 in chronic myelogenous leukaemia cells

“…Next, we detected several known lncRNAs involved in drug resistance in K562 and K562/ADM cells by qRT-PCR, such as HOTAIR [28], PVT1 [29], H19 [10], MALAT1 [30], UCA1 [11], CCAL [31], ANRIL [32], MEG3 [33] and FENDRR [12]. Interestingly, we found that FENDRR was mostly downregulated in K562/ADM cells compared with that in K562 cells ( Fig.…”

“…Long noncoding RNA (lncRNA) is a class of nonprotein coding transcripts longer than 200 nucleotides, which have been shown to play crucial roles in drug resistance [9]. For example lncRNA H19 plays a leading role through H19-CUL4A-ABCB1 pathway in breast cancer chemoresistance [10]. And lncRNA UCA1 can compete with MDR1 mRNA 3 0 UTR (untranslated region) for miR-16 in imatinib-resistant CML [11].…”

Recent Progress in Characterizing Long Noncoding RNAs in Cancer Drug Resistance

“…H19 also affects drug resistance in breast cancer via the H19-CUL4A-ABCB1/MDR1 pathway. Experimental results showed that knocking out H19 significantly increased MDR1 and MRP4 in Dox-resistant breast cancer cells, which identified the role of H19 in breast cancer resistance [16].…”