EBP50 suppresses the proliferation of MCF-7 human breast cancer cells via promoting Beclin-1/p62-mediated lysosomal degradation of c-Myc
EBP50 suppresses the proliferation of MCF-7 human breast cancer cells via promoting Beclin-1/p62-mediated lysosomal degradation of c-Myc
复制标题
EBP50 通过促进 Beclin-1/p62 介导的 c-Myc 溶酶体降解来抑制 MCF-7 人乳腺癌细胞的增殖。
DOI：
10.1038/aps.2017.171
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发表时间：
2018-08-01
影响因子：
8.2
通讯作者：
Shao, Rong-guang
中科院分区：
文献类型：
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作者：
Liu, Hong;Zhao, Wu-li;Shao, Rong-guang
c-Myc是细胞增殖和血管生成的关键激活剂，促进乳腺癌的发生和发展。Ezrin-radixin-moesin-binding phosphoprotein-50（EBP 50）是一种多功能支架蛋白，可抑制乳腺癌细胞的增殖。在这项研究中，我们研究了EBP 50的抑癌作用是否是由于其在体外和体内调节人乳腺癌MCF-7细胞中的c-Myc信号。我们首次发现乳腺癌组织中EBP 50和c-Myc表达水平之间存在显著相关性，并证明EBP 50通过降低MCF-7细胞中c-Myc及其下游蛋白cyclin A、E和Cdc 25 A的表达来抑制细胞增殖。我们进一步表明，EBP 50不调节c-Myc mRNA的表达，但它通过自噬溶酶体途径促进c-Myc的降解。此外，EBP 50促进c-Myc和自噬货物蛋白p62之间的整合，触发c-Myc的自噬溶酶体降解。在EBP 50沉默的MCF-7细胞中，Beclin-1激活自噬促进c-Myc降解并抑制细胞增殖。这些结果表明，EBP 50/Beclin-1/p62/c-Myc信号通路在MCF-7乳腺癌细胞的增殖中起作用：EBP 50刺激c-Myc的自噬溶酶体降解，从而抑制MCF-7细胞的增殖。基于我们的研究结果，促进溶酶体降解c-Myc可能是治疗乳腺癌的一个有前途的新策略。
c-Myc, a key activator of cell proliferation and angiogenesis, promotes the development and progression of breast cancer. Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) is a multifunctional scaffold protein that suppresses the proliferation of breast cancer cells. In this study we investigated whether the cancer-suppressing effects of EBP50 resulted from its regulation of c-Myc signaling in human breast cancer MCF-7 cells in vitro and in vivo. We first found a significant correlation between EBP50 and c-Myc expression levels in breast cancer tissue, and demonstrated that EBP50 suppressed cell proliferation through decreasing the expression of c-Myc and its downstream proteins cyclin A, E and Cdc25A in MCF-7 cells. We further showed that EBP50 did not regulate c-Myc mRNA expression, but it promoted the degradation of c-Myc through the autophagic lysosomal pathway. Moreover, EBP50 promoted integration between c-Myc and p62, an autophagic cargo protein, triggering the autophagic lysosomal degradation of c-Myc. In EBP50-silenced MCF-7 cells, activation of autophagy by Beclin-1 promoted the degradation of c-Myc and inhibited cell proliferation. These results demonstrate that the EBP50/Beclin-1/p62/c-Myc signaling pathway plays a role in the proliferation in MCF-7 breast cancer cells: EBP50 stimulates the autophagic lysosomal degradation of c-Myc, thereby inhibits the proliferation of MCF-7 cells. Based on our results, promoting the lysosomal degradation of c-Myc might be a promising new strategy for treating breast cancer.