CUL4B renders breast cancer cells tamoxifen-resistant via miR-32-5p/ER-alpha 36 axis
CUL4B renders breast cancer cells tamoxifen-resistant via miR-32-5p/ER-alpha 36 axis
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CUL4B 通过 miR-32-5p/ER-alpha 36 轴使乳腺癌细胞对他莫昔芬产生耐药性
DOI：
10.1002/path.5657
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发表时间：
2021
影响因子：
7.3
通讯作者：
Gong Yaoqin
中科院分区：
文献类型：
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作者：
Wang Yuxing;Pan Xiaohua;Li Yanjun;Wang Ru;Yang Yuanyuan;Jiang Baichun;Sun Gongping;Shao Changshun;Wang Molin;Gong Yaoqin
在雌激素受体（ER）阳性乳腺癌患者的内分泌治疗中，他莫昔芬（TAM）耐药性是一个重大的临床挑战。Cullin 4B （CUL4B）作为CUL4B - ring泛素连接酶复合物（CRL4B）的支架蛋白，在癌症中经常过表达，并通过多种表观遗传机制抑制肿瘤抑制因子。然而，CUL4B在调控耐药中的作用和潜在机制尚不清楚。在这里，我们发现CUL4B通过miR‐32‐5p/ER‐α36轴促进乳腺癌细胞的TAM耐药。我们发现CUL4B的上调与乳腺癌细胞TAM敏感性降低相关，CUL4B的下调或CUL4B显性阴性突变体的表达恢复了TAM耐药MCF7 - TAMRand T47D - tamr细胞对TAM的反应。在机制上，我们证明CUL4B通过上调ER - α36表达而使乳腺癌细胞产生TAM抗性，这是通过下调miR - 32 - 5p介导的。我们进一步发现，CRL4B通过催化H2AK119位点的单泛素化，并与PRC2和HDAC复合物协同促进miR‐32‐5p启动子H3K27位点的三甲基化，从表观遗传学上抑制miR‐32‐5p的转录。药物或遗传抑制CRL4B/PRC2/HDAC复合物可显著增加体外和体内乳腺癌细胞对TAM的敏感性。综上所述，我们的研究结果确定了CUL4B-miR‐32‐5p-ER‐α36轴在TAM耐药调控中的关键作用，并对TAM与CRL4B/PRC2/HDAC复合物抑制剂联合应用于乳腺癌治疗具有重要的治疗意义。©2021英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
Tamoxifen (TAM) resistance is a significant clinical challenge in endocrine therapies for estrogen receptor (ER)‐positive breast cancer patients. Cullin 4B (CUL4B), which acts as a scaffold protein in CUL4B–RING ubiquitin ligase complexes (CRL4B), is frequently overexpressed in cancer and represses tumor suppressors through diverse epigenetic mechanisms. However, the role and the underlying mechanisms of CUL4B in regulating drug resistance remain unknown. Here, we showed that CUL4B promotes TAM resistance in breast cancer cells through a miR‐32‐5p/ER‐α36 axis. We found that upregulation of CUL4B correlated with decreased TAM sensitivity of breast cancer cells, and knockdown of CUL4B or expression of a dominant‐negative CUL4B mutant restored the response to TAM in TAM‐resistant MCF7‐TAMRand T47D‐TAMRcells. Mechanistically, we demonstrated that CUL4B renders breast cancer cells TAM‐resistant by upregulating ER‐α36 expression, which was mediated by downregulation of miR‐32‐5p. We further showed that CRL4B epigenetically represses the transcription of miR‐32‐5p by catalyzing monoubiquitination at H2AK119 and coordinating with PRC2 and HDAC complexes to promote trimethylation at H3K27 at the promoter of miR‐32‐5p. Pharmacologic or genetic inhibition of CRL4B/PRC2/HDAC complexes significantly increased TAM sensitivity in breast cancer cellsin vitroandin vivo. Taken together, our findings thus establish a critical role for the CUL4B–miR‐32‐5p–ER‐α36 axis in the regulation of TAM resistance and have important therapeutic implications for combined application of TAM and the inhibitors of CRL4B/PRC2/HDAC complex in breast cancer treatment. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.