The endogenous retrovirus-derived long noncoding RNA TROJAN promotes triple-negative breast cancer progression via ZMYND8 degradation
The endogenous retrovirus-derived long noncoding RNA TROJAN promotes triple-negative breast cancer progression via ZMYND8 degradation
复制标题
内源性逆转录病毒衍生的长非编码RNA TROJAN通过ZMYND8降解促进三阴性乳腺癌进展
DOI：
10.1126/sciadv.aat9820
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发表时间：
2019-03-01
期刊：
影响因子：
13.6
通讯作者：
Shao, Zhi-Ming
中科院分区：
文献类型：
--
作者：
Jin, Xi;Xu, Xiao-En;Shao, Zhi-Ming
Herv基因座转录的lncRNA特洛伊木马通过泛素-蛋白酶体途径降解ZMYND8，促进TNBC的进展。人类内源性逆转录病毒(HERV)在乳腺癌的发生发展中起着关键作用。然而，非编码HERV的详细机制仍然难以捉摸。在这里，我们对HERV的全基因组转录组分析显示，一个灵长类的长非编码RNA，我们称之为特洛伊病毒，在人类三阴性乳腺癌(TNBC)中高度表达。特洛伊木马可促进TNBC的增殖和侵袭，并提示患者预后不良。我们进一步证实，特洛伊木马可以与转移抑制因子ZMYND8结合，并通过排斥ZNF592，通过泛素-蛋白酶体途径增加其降解。特洛伊还在表观遗传学上上调了多个细胞系中与转移相关的基因。特洛伊木马和ZMYND8之间的相关性随后在临床样本中得到证实。此外，我们的研究证实，针对特洛伊木马的反义寡核苷酸治疗在体内显著抑制了TNBC的进展。总之，长的非编码RNA特洛伊木马程序促进了TNBC的进展，并成为潜在的治疗靶点。
HERV loci transcribed lncRNA TROJAN promotes TNBC progression through ZMYND8 degradation by the ubiquitin-proteasome pathway. Human endogenous retroviruses (HERVs) play pivotal roles in the development of breast cancer. However, the detailed mechanisms of noncoding HERVs remain elusive. Here, our genome-wide transcriptome analysis of HERVs revealed that a primate long noncoding RNA, which we dubbed TROJAN, was highly expressed in human triple-negative breast cancer (TNBC). TROJAN promoted TNBC proliferation and invasion and indicated poor patient outcomes. We further confirmed that TROJAN could bind to ZMYND8, a metastasis-repressing factor, and increase its degradation through the ubiquitin-proteasome pathway by repelling ZNF592. TROJAN also epigenetically up-regulated metastasis-related genes in multiple cell lines. Correlations between TROJAN and ZMYND8 were subsequently confirmed in clinical samples. Furthermore, our study verified that antisense oligonucleotide therapy targeting TROJAN substantially suppressed TNBC progression in vivo. In conclusion, the long noncoding RNA TROJAN promotes TNBC progression and serves as a potential therapeutic target.