Abstract

Breast cancer is a common malignancy in women. Acquisition of drug resistance is one of the main obstacles encountered in breast cancer therapy. Long non-coding RNA (lncRNA) has been demonstrated to play vital roles in both development and tumorigenesis. However, the relationship between lncRNAs and the development of chemoresistance is not well established. In the present study, the high expression of lncRNA H19 was identified as a powerful factor associated with paclitaxel (PTX) resistance in ERα-positive breast cancer cells, but not in ERα-negative breast cancer cells. LncRNA H19 attenuated cell apoptosis in response to PTX treatment by inhibiting transcription of pro-apoptotic genes BIK and NOXA. H19 was further confirmed to suppress the promoter activity of BIK by recruiting EZH2 and by trimethylating the histone H3 at lysine 27. Interestingly, our data showed that lncRNA H19 was one of the downstream target molecules of ERα. Altered ERα expression may therefore change H19 levels to modulate the apoptosis response to chemotherapy in breast cancer cells. Our data suggest that the ERα-H19-BIK signaling axis plays an important role in promoting chemoresistance.

Highlights

  • Breast cancer is a common malignancy in women around the world

  • The expression level of Long non-coding RNA (lncRNA) H19 was positively correlated with PTX resistance in estrogen receptor α (ERα)-positive breast cancer cells

  • No upregulation of lncRNA H19 was observed in MDA-MB-231 resistant cells (Data not shown), which are ERα-negative breast cancer cells

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Summary

Introduction

Breast cancer is a common malignancy in women around the world. Chemotherapy has been an effective treatment plan for most breast cancer patients, the emergence of chemoresistance severely restrains the efficacy of this therapy. Increasing evidence supports a vital role for lncRNA in tumor formation. It could regulate multiple cancer-associated signaling pathways involved in cell cycle, cell proliferation, apoptosis, and migration [3,4,5,6,7,8]. H19 expression has been poorly studied in terms of cell apoptosis and chemoresistance. We have demonstrated an epigenetic inhibition of pro-apoptotic gene BIK by the association of H19 with the histone methyltransferase EZH2. This is the first confirmation of a role for H19 in breast cancer drug resistance

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