A novel Lnc408 maintains breast cancer stem cell stemness by recruiting SP3 to suppress CBY1 transcription and increasing nuclear β-catenin levels.
A novel Lnc408 maintains breast cancer stem cell stemness by recruiting SP3 to suppress CBY1 transcription and increasing nuclear β-catenin levels.
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一种新型 Lnc408 通过招募 SP3 抑制 CBY1 转录并增加核 β-连环蛋白水平来维持乳腺癌干细胞干细胞性
DOI：
10.1038/s41419-021-03708-6
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发表时间：
2021-05-01
影响因子：
9
通讯作者：
Tu G
中科院分区：
文献类型：
--
作者：
Wen S;Qin Y;Wang R;Yang L;Zeng H;Zhu P;Li Q;Qiu Y;Chen S;Liu Y;Hou Y;Tang X;Liu M;Tu G
肿瘤的发生、发展和复发可能与癌症干细胞（CSC）密切相关。维持 CSC 的复杂机制正在不断说明。长非编码 RNA (lncRNA) 由于其在各种生物过程中的多功能性，已被证明在 CSC 更新和干性维持中发挥着至关重要的作用。使用lncRNA阵列，我们在上皮-间质转化相关的乳腺CSC（BCSC）中鉴定出一种新型lncRNA（名为lnc408）。 lnc408 在体外和体内的 BCSC 中高表达。增强的 lnc408 对于 BCSC 特征和肿瘤发生至关重要。 Lnc408 可以将转录因子 SP3 招募到 CBY1 启动子，作为 BCSC 中 CBY1 转录的抑制剂。非 BCSC 中高表达的 CBY1 与 14-3-3 和 β-catenin 相互作用形成三元复合物，导致三元复合物从细胞核易位到细胞质，并以磷酸化依赖性模式降解 β-catenin。 BCSC 中 lnc408 介导的 CBY1 减少会损害 14-3-3/β-catenin/CBY1 复合物的形成，并将 β-catenin 保留在细胞核中，促进 CSC 相关 CD44、SOX2、Nanog、Klf4 和 c-Myc 表达，并有助于乳腺球的形成；然而，肿瘤细胞中CBY1表达的恢复会降低BCSC及其富集，因此lnc408在维持BCSC干性中发挥重要作用。简而言之，这些发现强调了新型 lnc408 通过招募 SP3 抑制 CBY1 表达和细胞核内 β-catenin 积累来维持 BCSC 的干性特性，从而发挥致癌因子的作用。 Lnc408-CBY1-β-catenin信号轴可能成为乳腺癌新的诊断和治疗靶点。
Tumor initiation, development, and relapse may be closely associated with cancer stem cells (CSCs). The complicated mechanisms underlying the maintenance of CSCs are keeping in illustration. Long noncoding RNAs (lncRNAs), due to their multifunction in various biological processes, have been indicated to play a crucial role in CSC renewal and stemness maintenance. Using lncRNA array, we identified a novel lncRNA (named lnc408) in epithelial–mesenchymal transition-related breast CSCs (BCSCs). The lnc408 is high expressed in BCSCs in vitro and in vivo. The enhanced lnc408 is critical to BCSC characteristics and tumorigenesis. Lnc408 can recruit transcript factor SP3 to CBY1 promoter to serve as an inhibitor in CBY1 transcription in BCSCs. The high expressed CBY1 in non-BCSC interacts with 14-3-3 and β-catenin to form a ternary complex, which leads a translocation of the ternary complex into cytoplasm from nucleus and degradation of β-catenin in phosphorylation-dependent pattern. The lnc408-mediated decrease of CBY1 in BCSCs impairs the formation of 14-3-3/β-catenin/CBY1 complex, and keeps β-catenin in nucleus to promote CSC-associated CD44, SOX2, Nanog, Klf4, and c-Myc expressions and contributes to mammosphere formation; however, restoration of CBY1 expression in tumor cells reduces BCSC and its enrichment, thus lnc408 plays an essential role in maintenance of BCSC stemness. In shortly, these findings highlight that the novel lnc408 functions as an oncogenic factor by recruiting SP3 to inhibit CBY1 expression and β-catenin accumulation in nucleus to maintain stemness properties of BCSCs. Lnc408–CBY1–β-catenin signaling axis might serve as a new diagnostic and therapeutic target for breast cancer.
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影响因子：
28.2
作者：
Liu X;Taftaf R;Kawaguchi M;Chang YF;Chen W;Entenberg D;Zhang Y;Gerratana L;Huang S;Patel DB;Tsui E;Adorno-Cruz V;Chirieleison SM;Cao Y;Harney AS;Patel S;Patsialou A;Shen Y;Avril S;Gilmore HL;Lathia JD;Abbott DW;Cristofanilli M;Condeelis JS;Liu H
通讯作者：
Liu H
影响因子：
28.2
作者：
Haricharan S;Punturi N;Singh P;Holloway KR;Anurag M;Schmelz J;Schmidt C;Lei JT;Suman V;Hunt K;Olson JA Jr;Hoog J;Li S;Huang S;Edwards DP;Kavuri SM;Bainbridge MN;Ma CX;Ellis MJ
通讯作者：
Ellis MJ
影响因子：
4.3
作者：
Schuierer, Marion M.;Graf, Elisabeth;Bosserhoff, Anja-Katrin
通讯作者：
Bosserhoff, Anja-Katrin
影响因子：
7.4
作者：
Fu, Tao;Ji, Ke;Ji, Jiafu
通讯作者：
Ji, Jiafu
DOI：
10.1073/pnas.0910009106
发表时间：
2009-11-10
影响因子：
11.1
作者：
Liu, Manran;Casimiro, Mathew C.;Pestell, Richard G.
通讯作者：
Pestell, Richard G.