Kim Clara Yuri, Oh Ji Hoon, Lee Ji-Yeon, Kim Myoung Hee
Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul 03722, Korea.
Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
J Cancer. 2020 Mar 13;11(12):3416-3423. doi: 10.7150/jca.38728. eCollection 2020.
Breast cancer is one of the most commonly diagnosed cancers in women worldwide. Approximately 40% of patients with breast cancer acquire endocrine resistance following therapy with tamoxifen. Many explanations for the development of endocrine resistance have been put forward, one of them being the dysregulation of long non-coding RNAs (lncRNAs). The lncRNA HOTAIRM1, known to be involved in myelopoiesis as well as transcriptional regulation of the HOXA genes in embryonic stem cells, is also expressed in breast cancer cells. This study explored the molecular mechanisms of HOTAIRM1 involved in acquired tamoxifen resistance. We showed that HOTAIRM1 and HOXA1 are concurrently up-regulated in tamoxifen-resistant MCF7 (TAMR) cells. Knockdown of HOTAIRM1 down-regulated HOXA1 expression and restored sensitivity to tamoxifen. In addition, the knockdown of HOXA1 showed similar effects, suggesting that the HOTAIRM1/HOXA1 axis regulates tamoxifen resistance. Furthermore, we showed that HOTAIRM1 directly interacts with EZH2 and prevents the PRC2 complex from binding and depositing H3K27me3 on the putative promoter of HOXA1. Together, our findings suggest that HOXA1 and its neighboring lncRNA, HOTAIRM1, might serve as potential therapeutic targets for ER+ breast cancer patients who have acquired tamoxifen resistance.
乳腺癌是全球女性中最常被诊断出的癌症之一。大约40%的乳腺癌患者在接受他莫昔芬治疗后会产生内分泌抵抗。对于内分泌抵抗的发生提出了许多解释，其中之一是长链非编码RNA（lncRNA）的失调。lncRNA HOTAIRM1已知参与骨髓生成以及胚胎干细胞中HOXA基因的转录调控，在乳腺癌细胞中也有表达。本研究探讨了HOTAIRM1参与获得性他莫昔芬耐药的分子机制。我们发现HOTAIRM1和HOXA1在他莫昔芬耐药的MCF7（TAMR）细胞中同时上调。敲低HOTAIRM1可下调HOXA1表达并恢复对他莫昔芬的敏感性。此外，敲低HOXA1也显示出类似的效果，表明HOTAIRM1/HOXA1轴调节他莫昔芬耐药。此外，我们发现HOTAIRM1直接与EZH2相互作用，并阻止PRC2复合物结合并在HOXA1的假定启动子上沉积H3K27me3。总之，我们的研究结果表明，HOXA1及其邻近的lncRNA HOTAIRM1可能作为获得性他莫昔芬耐药的ER +乳腺癌患者的潜在治疗靶点。
