PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression.
PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression.
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DOI：
10.1016/j.celrep.2017.11.096
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发表时间：
2017-12-19
期刊：
影响因子：
8.8
通讯作者：
Davies CC
中科院分区：
文献类型：
--
作者：
Chiang K;Zielinska AE;Shaaban AM;Sanchez-Bailon MP;Jarrold J;Clarke TL;Zhang J;Francis A;Jones LJ;Smith S;Barbash O;Guccione E;Farnie G;Smalley MJ;Davies CC
乳腺癌进展、治疗耐药性和复发被认为起源于一小群肿瘤细胞，即乳腺癌干细胞（BCSC）。因此，确定BCSC功能的关键因素对于开发治疗至关重要。在这里，我们确定了精氨酸甲基转移酶PRMT 5作为一个关键的体外和体内调节BCSC增殖和自我更新，并建立FOXP 1，翼螺旋/叉头转录因子，作为一个关键的效应PRMT 5诱导BCSC功能。从机制上讲，PRMT 5募集到FOXP 1启动子促进H3 R2 me 2s、SET 1募集、H3 K4 me 3和基因表达。我们的发现具有临床意义，因为在已建立的肿瘤异种移植物内的PRMT 5耗竭或用临床前PRMT 5抑制剂治疗患者来源的BCSC显著减少了BCSC数量。总之，我们的研究结果强调了PRMT 5在BCSC维持中的重要性，并表明PRMT 5或下游靶点的小分子抑制剂可能是消除这种致癌人群的有效策略。PRMT 5在乳腺癌干细胞（BCSC）中表达升高PRMT 5是BCSC功能和体外和体内自我更新所需的在已建立的肿瘤中靶向PRMT 5减少干细胞数量和肿瘤生长FOXP 1启动子被PRMT 5甲基化并且是PRMT 5驱动的BCSC功能的效应子Chiang et al.显示精氨酸甲基转移酶PRMT 5有助于乳腺癌干细胞功能，部分通过组蛋白甲基化调节FOXP 1表达。通过消耗或抑制PRMT 5来靶向PRMT 5降低了体外和体内干细胞频率，暗示PRMT 5在乳腺癌发病机制中是重要的。
Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population. PRMT5 expression is elevated in breast cancer stem cells (BCSCs) PRMT5 is required for BCSC function and self-renewal in vitro and in vivo Targeting PRMT5 in an established tumor reduces stem cell numbers and tumor growth FOXP1 promoter is methylated by PRMT5 and is an effector of PRMT5-driven BCSC function Chiang et al. show that the arginine methyltransferase PRMT5 contributes to breast cancer stem cell function, in part through histone methylation regulating FOXP1 expression. Targeting of PRMT5 through depletion or inhibition reduces stem cell frequency in vitro and in vivo, implicating PRMT5 as important in breast cancer pathogenesis.
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