YY1-MIR372-SQSTM1 regulatory axis in autophagy
YY1-MIR372-SQSTM1 regulatory axis in autophagy
复制标题
DOI：
10.4161/auto.29486
复制
发表时间：
2014-08-01
期刊：
影响因子：
13.3
通讯作者：
Jin, Hongchuan
中科院分区：
文献类型：
--
作者：
Feng, Lifeng;Ma, Yanning;Jin, Hongchuan
自噬是一种降解细胞内物质以使细胞在不利条件下存活的自我蛋白分解过程。然而，自噬是如何在人类致癌过程中被激活的，在很大程度上仍不清楚。在这里，我们报告了一种对人类癌细胞自噬的表观遗传调控。YY1(YY1转录因子)是一种众所周知的表观遗传调节因子，在许多癌症中表达上调。我们发现YY1基因敲除通过下调SQSTM1(隔离小体1)来抑制细胞活力和自噬通量。YY1通过对MIR372(MicroRNA372)转录的表观遗传调控来调控SQSTM1的表达。在营养饥饿期间，YY1被刺激通过抑制MIR372的表达来促进SQSTM1的表达和随后的自噬激活。与YY1缺失类似，MIR372的过表达阻止了自噬激活，并抑制了体内肿瘤的生长。因此，SQSTM1的上调和合适的自噬通量有助于YY1的致癌作用。YY1促进的SQSTM1上调可能成为检测肿瘤的有用组织学标志物和药物开发的潜在靶点。
Autophagy is a self-proteolytic process that degrades intracellular material to enable cellular survival under unfavorable conditions. However, how autophagy is activated in human carcinogenesis remains largely unknown. Herein we report an epigenetic regulation of autophagy in human cancer cells. YY1 (YY1 transcription factor) is a well-known epigenetic regulator and is upregulated in many cancers. We found that YY1 knockdown inhibited cell viability and autophagy flux through downregulating SQSTM1 (sequestosome 1). YY1 regulated SQSTM1 expression through the epigenetic modulation of the transcription of MIR372 (microRNA 372) which was found to target SQSTM1 directly. During nutrient starvation, YY1 was stimulated to promote SQSTM1 expression and subsequent autophagy activation by suppressing MIR372 expression. Similar to YY1 depletion, MIR372 overexpression blocked autophagy activation and inhibited in vivo tumor growth. SQSTM1 upregulation and competent autophagy flux thus contributed to the oncogenic function of YY1. YY1-promoted SQSTM1 upregulation might be a useful histological marker for cancer detection and a potential target for drug development.