超級(jí)增強(qiáng)子在腫瘤研究中的進(jìn)展

吳志強(qiáng)，米澤云

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超級(jí)增強(qiáng)子在腫瘤研究中的進(jìn)展

吳志強(qiáng)1,2，米澤云3

1. 天津醫(yī)科大學(xué)腫瘤醫(yī)院，放射治療科，天津 300060 2. 國(guó)家腫瘤臨床醫(yī)學(xué)研究中心，天津市“腫瘤防治”重點(diǎn)實(shí)驗(yàn)室，天津市惡性腫瘤臨床醫(yī)學(xué)研究中心，天津 300060 3. 天津醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院，生物化學(xué)與分子生物學(xué)系，天津 300070

超級(jí)增強(qiáng)子是由多個(gè)相鄰近的普通增強(qiáng)子組成的、驅(qū)動(dòng)調(diào)控細(xì)胞身份基因表達(dá)的一個(gè)大簇，該區(qū)域富集高密度的轉(zhuǎn)錄因子、輔因子及增強(qiáng)子相關(guān)表觀修飾。超級(jí)增強(qiáng)子所驅(qū)動(dòng)的異常轉(zhuǎn)錄基因?qū)S持腫瘤細(xì)胞特性至關(guān)重要。腫瘤細(xì)胞通過(guò)組裝自身超級(jí)增強(qiáng)子，顯著促進(jìn)多種癌基因表達(dá)，從而增強(qiáng)腫瘤細(xì)胞的增殖、侵襲和轉(zhuǎn)移的能力；抑制超級(jí)增強(qiáng)子的活性，則顯著抑制腫瘤細(xì)胞的生長(zhǎng)和存活。本文對(duì)目前報(bào)道的腫瘤細(xì)胞中超級(jí)增強(qiáng)子的結(jié)構(gòu)特征和功能調(diào)控，以及靶向超級(jí)增強(qiáng)子藥物研發(fā)現(xiàn)狀進(jìn)行了總結(jié)，旨在為研發(fā)新的針對(duì)超級(jí)增強(qiáng)子為靶點(diǎn)的抗腫瘤藥物提供理論基礎(chǔ)和借鑒。

增強(qiáng)子；超級(jí)增強(qiáng)子；轉(zhuǎn)錄；癌癥

20世紀(jì)80年代，研究發(fā)現(xiàn)SV40病毒的一段DNA序列對(duì)于家兔()的β-珠蛋白(β-globin，一種能夠通過(guò)鐵卟啉環(huán)可逆性結(jié)合氧的呼吸性蛋白質(zhì))的轉(zhuǎn)錄具有增強(qiáng)作用，因此將這一段DNA稱為增強(qiáng)子(enhancer)[1]。隨后的研究發(fā)現(xiàn)在哺乳動(dòng)物細(xì)胞內(nèi)也存在類似特性的DNA序列，可以遠(yuǎn)距離、無(wú)方向性的增強(qiáng)基因轉(zhuǎn)錄[2~4]。近30年研究證明增強(qiáng)子具有以下特征(圖1)[2~5]：(1) 增強(qiáng)子DNA序列處于染色體疏松的區(qū)域，與核小體中組蛋白的修飾，轉(zhuǎn)錄因子的結(jié)合有關(guān)；(2) 增強(qiáng)子活性與其DNA序列結(jié)合的組蛋白H3的第4位賴氨酸單甲基化(H3K4me1)和第27位賴氨酸乙?；?H3K27ac)修飾程度成正相關(guān)[6]；(3) 增強(qiáng)子發(fā)揮功能需要增強(qiáng)子區(qū)域和啟動(dòng)子的區(qū)域的直接相互作用，形成三維環(huán)狀結(jié)構(gòu)(3D-loop)。增強(qiáng)子和啟動(dòng)子的相互作用由多種蛋白介導(dǎo)，如Mediator復(fù)合體、Cohesin等[6,7]。

隨著DNA測(cè)序技術(shù)的發(fā)展，人類對(duì)基因有了進(jìn)一步的認(rèn)識(shí)，對(duì)于增強(qiáng)子的研究也越來(lái)越深入。2013年，美國(guó)Young R.A.教授(Whitehead Institute for Biomedical Research)基于當(dāng)時(shí)增強(qiáng)子的研究首次提出超級(jí)增強(qiáng)子(super enhancers，SEs)這一概念。他們發(fā)現(xiàn)胚胎干細(xì)胞(embryonic stem cells，ESC)的主要轉(zhuǎn)錄因子結(jié)合在一些特殊的增強(qiáng)子上，這些特殊的增強(qiáng)子對(duì)于維持胚胎干細(xì)胞的干性至關(guān)重要，并將這些特殊的增強(qiáng)子定義為超級(jí)增強(qiáng)子[8]。超級(jí)增強(qiáng)子簡(jiǎn)單來(lái)說(shuō)就是由多個(gè)增強(qiáng)子組成的一個(gè)大簇，富集高密度的轉(zhuǎn)錄因子、輔因子和增強(qiáng)子表觀修飾。它和普通增強(qiáng)子在序列大小、轉(zhuǎn)錄因子的結(jié)合密度、激活轉(zhuǎn)錄的能力以及對(duì)轉(zhuǎn)錄因子抑制劑的敏感性均不同[8]。隨后的研究不僅發(fā)現(xiàn)超級(jí)增強(qiáng)子存在于多種細(xì)胞類型中，也進(jìn)一步明確了超級(jí)增強(qiáng)子區(qū)別于普通增強(qiáng)子的功能特性(圖2)[6]：(1) 超級(jí)增強(qiáng)子具有高密度的H3K27ac和H3K4me1修飾，以及Mediator復(fù)合體和Bromodomain containing 4蛋白(BRD4，與組蛋白乙?；揎椢稽c(diǎn)結(jié)合)的結(jié)合；(2) 超級(jí)增強(qiáng)子結(jié)合的轉(zhuǎn)錄因子以及與轉(zhuǎn)錄活性相關(guān)的染色體的標(biāo)記比普通增強(qiáng)子高很多；(3) 超級(jí)增強(qiáng)子調(diào)控的基因比普通增強(qiáng)子調(diào)控的基因表達(dá)水平高很多；(4) 組成超級(jí)增強(qiáng)子的單個(gè)增強(qiáng)子也可以像普通增強(qiáng)子一樣激活基因轉(zhuǎn)錄；(5) 超級(jí)增強(qiáng)子可以結(jié)合組織中特異的轉(zhuǎn)錄因子；(6) 與普通增強(qiáng)子相比，超級(jí)增強(qiáng)子活性對(duì)于轉(zhuǎn)錄因子的阻斷更敏感[9,10]。這些現(xiàn)象支持一個(gè)假說(shuō)：超級(jí)增強(qiáng)子發(fā)揮功能需要結(jié)合到超級(jí)增強(qiáng)子上的轉(zhuǎn)錄因子的合作協(xié)同，具有大量轉(zhuǎn)錄因子結(jié)合的增強(qiáng)子對(duì)于基因轉(zhuǎn)錄的調(diào)控會(huì)對(duì)轉(zhuǎn)錄因子濃度的改變更敏感[11](圖2)。有趣的是，富集在超級(jí)增強(qiáng)子上的主要的轉(zhuǎn)錄因子也受超級(jí)增強(qiáng)子的調(diào)控轉(zhuǎn)錄，這就意味著超級(jí)增強(qiáng)子調(diào)控基因轉(zhuǎn)錄存在正反饋協(xié)同作用，也就形成了細(xì)胞中的核心轉(zhuǎn)錄調(diào)控環(huán)路(coretranscriptionregulatorycircuitry, CRC)[12,13]。正是由于超級(jí)增強(qiáng)子調(diào)控基因表達(dá)的特性和其敏感性，因而才能夠協(xié)調(diào)細(xì)胞在生長(zhǎng)、發(fā)育、分化和疾病等各種狀態(tài)的過(guò)渡[9,14~16]。本文主要從超級(jí)增強(qiáng)子與腫瘤細(xì)胞的關(guān)系、在腫瘤細(xì)胞中的調(diào)控以及該靶點(diǎn)藥物在腫瘤治療中的現(xiàn)狀這3個(gè)方面闡述超級(jí)增強(qiáng)子在腫瘤細(xì)胞中的作用。

圖1 增強(qiáng)子的結(jié)構(gòu)特征和功能

A：增強(qiáng)子的結(jié)構(gòu)特征和表觀修飾。增強(qiáng)子區(qū)域染色體比較疏松，部分DNA暴露并且富集轉(zhuǎn)錄因子；增強(qiáng)子區(qū)域H3組蛋白具有H3K4me1和H3K27ac修飾。B：轉(zhuǎn)錄因子結(jié)合到增強(qiáng)子區(qū)域之后進(jìn)一步招募Mediator復(fù)合體，其主要介導(dǎo)增強(qiáng)子與PolⅡ相互作用，這樣增強(qiáng)子與啟動(dòng)子之間形成三維環(huán)狀結(jié)構(gòu)，從而增強(qiáng)基因的轉(zhuǎn)錄水平。

1 超級(jí)增強(qiáng)子與腫瘤的關(guān)系

2013年，Young R.A.教授發(fā)現(xiàn)在多發(fā)性骨髓瘤細(xì)胞中超級(jí)增強(qiáng)子的區(qū)域募集了高濃度的Mediator復(fù)合體和BRD4[17]，這意味著在多發(fā)性骨髓瘤細(xì)胞中超級(jí)增強(qiáng)子處于活化狀態(tài)。功能分析實(shí)驗(yàn)表明，超級(jí)增強(qiáng)子調(diào)控的基因(、、、)對(duì)于多發(fā)性骨髓瘤的發(fā)生和發(fā)展起到關(guān)鍵的促進(jìn)作用[17]。后續(xù)研究發(fā)現(xiàn)，超級(jí)增強(qiáng)子在多種腫瘤中均有報(bào)道，如彌漫性大B細(xì)胞淋巴瘤[18]、T細(xì)胞急性淋巴細(xì)胞白血病[19,20]、默克爾細(xì)胞癌[21]、急性髓性白血病[22]、小細(xì)胞肺癌[10]、卵巢癌[23]、上皮癌[24]、鱗狀細(xì)胞癌[25]、黑色素瘤[15]、乳腺癌[26]、食管鱗狀細(xì)胞癌[27]和結(jié)腸癌[28]等。在腫瘤細(xì)胞中超級(jí)增強(qiáng)子調(diào)控的關(guān)鍵癌基因在正常細(xì)胞中是不表達(dá)的，這就提示超級(jí)增強(qiáng)子通過(guò)調(diào)控這些基因而對(duì)腫瘤生成和腫瘤特性維持起到關(guān)鍵作用[9,29,30]。由于細(xì)胞在癌變過(guò)程中大多數(shù)的超級(jí)增強(qiáng)子是重新形成具有功能性的元件，因此超級(jí)增強(qiáng)子的活化可以作為細(xì)胞癌變的一種標(biāo)志[9,29,30]。綜上所述目前研究均表明超級(jí)增強(qiáng)子的激活可以促使正常細(xì)胞向腫瘤細(xì)胞的惡性轉(zhuǎn)化。

超級(jí)增強(qiáng)子不但對(duì)蛋白編碼基因具有轉(zhuǎn)錄激活作用，對(duì)非編碼基因，如microRNA (miRNA，一種長(zhǎng)度約22nt的小RNA)的轉(zhuǎn)錄及成熟也具有調(diào)控功能。美國(guó)麻省理工學(xué)院生物系Phillip A. S.教授研究組利用CRISPR/Cas9基因組編輯方法發(fā)現(xiàn)超級(jí)增強(qiáng)子不僅促進(jìn)miRNA的轉(zhuǎn)錄，也可以通過(guò)招募Drosha/DGCR8蛋白復(fù)合體促進(jìn)前體miRNA (pri- miRNA)的成熟，以此來(lái)調(diào)控細(xì)胞種類特異性miRNA的生成[31]。對(duì)18種腫瘤細(xì)胞分析發(fā)現(xiàn)，在有些腫瘤細(xì)胞中超級(jí)增強(qiáng)子活性上調(diào)，而有些腫瘤細(xì)胞中超級(jí)增強(qiáng)子活性下降。進(jìn)一步分析表明在細(xì)胞癌變過(guò)程中激活的超級(jí)增強(qiáng)子往往與促癌miRNA相關(guān)，而失活的超級(jí)增強(qiáng)子主要調(diào)控抑癌miRNA的生成[31]。以上研究提示，調(diào)控miRNA的超級(jí)增強(qiáng)子活性與腫瘤發(fā)生發(fā)展密切相關(guān)。因此，超級(jí)增強(qiáng)子聯(lián)合多個(gè)miRNA (SE-miRNA)將有潛力成為細(xì)胞癌變的生物標(biāo)志物[31]，對(duì)于腫瘤的早期診斷以及治療具有重要的臨床意義。除此之外，超級(jí)增強(qiáng)子還可以調(diào)控長(zhǎng)鏈非編碼RNA (long non-coding RNA, lncRNA)的轉(zhuǎn)錄[32]。在鱗狀細(xì)胞癌組織中發(fā)現(xiàn)受超級(jí)增強(qiáng)子調(diào)控的lncRNA LINC01503明顯上調(diào)。進(jìn)一步研究發(fā)現(xiàn)，LINC01503的表達(dá)水平與鱗狀細(xì)胞癌病人預(yù)后呈負(fù)相關(guān)：LINC01503高表達(dá)的病人生存率低。研究表明激活的增強(qiáng)子或超級(jí)增強(qiáng)子區(qū)域也可以被轉(zhuǎn)錄產(chǎn)生RNA，稱為enhancer RNA (eRNA)，eRNA可以協(xié)同超級(jí)增強(qiáng)子激活轉(zhuǎn)錄[33,34]。超級(jí)增強(qiáng)子發(fā)揮功能不僅依賴于和啟動(dòng)子之間的3D-loop的形成，也依賴于超級(jí)增強(qiáng)子轉(zhuǎn)錄的eRNA的生成。因此，在臨床上可以結(jié)合lncRNA以及eRNA的水平對(duì)病人進(jìn)行精準(zhǔn)治療。

圖2 超級(jí)增強(qiáng)子的結(jié)構(gòu)

超級(jí)增強(qiáng)子是由多個(gè)增強(qiáng)子組成的一個(gè)大簇。組成超級(jí)增強(qiáng)子的單個(gè)增強(qiáng)子基因組的距離比較近，它們均可以獨(dú)立的結(jié)合轉(zhuǎn)錄因子、Mediator復(fù)合體等輔因子，共同調(diào)控同一啟動(dòng)子的轉(zhuǎn)錄活性。

腫瘤的異質(zhì)性很大一方面是由于一個(gè)腫瘤內(nèi)的細(xì)胞通?？赡軄?lái)源于多個(gè)不同的細(xì)胞克隆，而這些不同克隆來(lái)源的腫瘤細(xì)胞其超級(jí)增強(qiáng)子的激活也存在差異，這就為區(qū)分腫瘤亞型或腫瘤細(xì)胞亞群提供了一種新的鑒定方法。例如，通過(guò)以往的方法對(duì)成神經(jīng)管細(xì)胞瘤的生物化學(xué)和遺傳學(xué)分析把其分成4個(gè)亞型。但是通過(guò)對(duì)這4個(gè)亞型的增強(qiáng)子圖譜分析發(fā)現(xiàn)了一種新的亞型，這種新型的成神經(jīng)管細(xì)胞瘤細(xì)胞中都具有與腫瘤異質(zhì)性相關(guān)的超級(jí)增強(qiáng)子群[35]。更為重要的是通過(guò)分析在這類腫瘤細(xì)胞的超級(jí)增強(qiáng)子調(diào)控的轉(zhuǎn)錄因子可以明確細(xì)胞特異性的核心轉(zhuǎn)錄調(diào)控環(huán)路(CRC)。通過(guò)對(duì)于CRC分析確定了LIM homeobox transcription factor 1 alpha (LMX1A，一種轉(zhuǎn)錄因子)在第4類亞型的成神經(jīng)管細(xì)胞瘤是一個(gè)主要轉(zhuǎn)錄因子(master transcription factor)[36]。同樣，在其他基因異質(zhì)性癌中也發(fā)現(xiàn)類似情況，如三陰性乳腺癌依靠超級(jí)增強(qiáng)子調(diào)控的特異性的基因群來(lái)維持細(xì)胞生長(zhǎng)和增殖[26]?？梢?jiàn)通過(guò)對(duì)于不同腫瘤細(xì)胞的增強(qiáng)子的圖譜分析可以獨(dú)立預(yù)測(cè)腫瘤亞型，發(fā)現(xiàn)之前治療的不足以及新的潛在治療靶點(diǎn)，為腫瘤治療提供新思路、新方向[6]。

綜上所述，在多種腫瘤細(xì)胞中均發(fā)現(xiàn)超級(jí)增強(qiáng)子處于異常激活狀態(tài)，其對(duì)于靶基因的調(diào)控呈多樣化：促進(jìn)mRNA的生成、促進(jìn)miRNA的轉(zhuǎn)錄以及成熟、促進(jìn)lncRNA的轉(zhuǎn)錄生成以及超級(jí)增強(qiáng)子自身轉(zhuǎn)錄生成的eRNA對(duì)于其活性也起到協(xié)同作用。除此之外，通過(guò)繪制腫瘤細(xì)胞的增強(qiáng)子圖譜可以預(yù)測(cè)腫瘤亞型，為基因異質(zhì)性腫瘤提供統(tǒng)一的治療 平臺(tái)。

2 腫瘤細(xì)胞中超級(jí)增強(qiáng)子的調(diào)控

在腫瘤細(xì)胞中超級(jí)增強(qiáng)子的調(diào)控是如何實(shí)現(xiàn)的呢？早期對(duì)于小鼠胚胎干細(xì)胞發(fā)育的研究提出一個(gè)模型：組成超級(jí)增強(qiáng)子的每一個(gè)增強(qiáng)子都具有活性，而超級(jí)增強(qiáng)子的功能類似于一個(gè)平臺(tái)，這個(gè)平臺(tái)匯集了與發(fā)育相關(guān)的信號(hào)通路傳遞過(guò)來(lái)的信號(hào)，這些信號(hào)協(xié)同調(diào)控超級(jí)增強(qiáng)子活性啟動(dòng)基因轉(zhuǎn)錄(圖3)[11]。同樣，與癌基因相關(guān)的超級(jí)增強(qiáng)子也富集了腫瘤細(xì)胞依賴的信號(hào)通路的轉(zhuǎn)錄因子。在Wnt信號(hào)通路異常引起的結(jié)腸癌細(xì)胞中，相關(guān)的超級(jí)增強(qiáng)子區(qū)域富集了很多由Wnt信號(hào)通路終端的轉(zhuǎn)錄因子4 (tra-nscription factor 4, TCF4)，通過(guò)激活或者抑制Wnt信號(hào)通路，可以控制超級(jí)增強(qiáng)子調(diào)控的基因轉(zhuǎn)錄[11,37]。在雌激素受體(estrogen receptor, ER)陽(yáng)性的乳腺癌細(xì)胞中，相關(guān)的超級(jí)增強(qiáng)子區(qū)域聚集了大量的ERα；而在三陰性乳腺癌細(xì)胞中缺少類固醇激素的表達(dá)，與其相關(guān)的超級(jí)增強(qiáng)子區(qū)域富集了完全不同的轉(zhuǎn)錄因子[26,37]。

在腫瘤細(xì)胞中，信號(hào)通路從多方面對(duì)超級(jí)增強(qiáng)子的活性進(jìn)行調(diào)控。2015年美國(guó)西北大學(xué)Licht J.D. 教授團(tuán)隊(duì)研究發(fā)現(xiàn)Ras-Erk活性與超級(jí)增強(qiáng)子的活性密切相關(guān)：抑制Ras蛋白的活性會(huì)導(dǎo)致超級(jí)增強(qiáng)子相關(guān)的特征(如H3K27ac)消失、活性下降、降低相關(guān)基因轉(zhuǎn)錄；激活Ras可以增強(qiáng)調(diào)控癌基因的超級(jí)增強(qiáng)子活性[38]。另一方面，促癌信號(hào)通路可以通過(guò)操縱轉(zhuǎn)錄機(jī)器調(diào)節(jié)超級(jí)增強(qiáng)子的活性。轉(zhuǎn)錄暫停是激活的RNA聚合酶Ⅱ(RNA polymerase Ⅱ，Pol Ⅱ)在啟動(dòng)子附近停止轉(zhuǎn)錄的一種狀態(tài)[39]。在正常的肝細(xì)胞中，Hippo信號(hào)通路可以通過(guò)限制暫停的Pol Ⅱ釋放，因而抑制了增強(qiáng)子或超級(jí)增強(qiáng)子調(diào)控的基因轉(zhuǎn)錄[40]。然而，在肝癌細(xì)胞中Hippo信號(hào)通路的缺失導(dǎo)致YAP(Yes associated protein)入核，YAP蛋白結(jié)合到超級(jí)增強(qiáng)子上，招募Mediator復(fù)合體和細(xì)胞周期素依賴性激酶9(Cyclin-dependent kinase 9，CDK9)，使暫停的Pol Ⅱ進(jìn)入到延伸狀態(tài)，促進(jìn)癌基因轉(zhuǎn)錄[41]。因此，在肝癌中YAP通過(guò)激活超級(jí)增強(qiáng)子促進(jìn)癌基因的轉(zhuǎn)錄。

圖3 信號(hào)通路對(duì)于超級(jí)增強(qiáng)子與普通增強(qiáng)子的調(diào)控

A：組成超級(jí)增強(qiáng)子的每一個(gè)增強(qiáng)子都具有活性，每個(gè)增強(qiáng)子富集了各種信號(hào)通路終端轉(zhuǎn)錄因子，這些轉(zhuǎn)錄因子協(xié)同調(diào)控基因轉(zhuǎn)錄；B：普通增強(qiáng)子只富集一種信號(hào)通路的終端轉(zhuǎn)錄因子。

以上研究表明超級(jí)增強(qiáng)子可以作為連接癌基因信號(hào)通路和維持腫瘤細(xì)胞特性的基因轉(zhuǎn)錄表達(dá)的渠道。然而進(jìn)一步研究發(fā)現(xiàn)信號(hào)通路對(duì)于超級(jí)增強(qiáng)子的調(diào)控與轉(zhuǎn)錄因子在超級(jí)增強(qiáng)子區(qū)動(dòng)態(tài)結(jié)合有關(guān)。例如，在NOTCH1異常導(dǎo)致的T細(xì)胞白血病(T-ALL)細(xì)胞中，NOTCH1在基因組上具有普遍的結(jié)合，但是只有不到10%的基因?qū)τ贜OTCH1信號(hào)通路的改變有應(yīng)答，而這些應(yīng)答基因的NOTCH1結(jié)合在對(duì)應(yīng)的超級(jí)增強(qiáng)子上。如果這些位點(diǎn)丟失NOTCH1的結(jié)合就會(huì)導(dǎo)致超級(jí)增強(qiáng)子的特征消失[42]。

3 針對(duì)超級(jí)增強(qiáng)子在腫瘤治療中的作用

在腫瘤細(xì)胞中癌基因被轉(zhuǎn)錄激活，進(jìn)而介導(dǎo)細(xì)胞的增殖和永生化[29,30]。因此，抑制癌基因的轉(zhuǎn)錄是一個(gè)潛在的治療靶點(diǎn)。但是針對(duì)這一靶點(diǎn)面臨著巨大的挑戰(zhàn)：轉(zhuǎn)錄是細(xì)胞最基本的功能，對(duì)癌基因的轉(zhuǎn)錄抑制可能會(huì)引起細(xì)胞基因轉(zhuǎn)錄的廣譜抑制[43]。因此，臨床上用到的轉(zhuǎn)錄抑制劑應(yīng)該特異性的抑制癌基因，對(duì)于正常細(xì)胞的轉(zhuǎn)錄影響不大[6,44~46]。

轉(zhuǎn)錄起始、暫停、延伸等過(guò)程的有序轉(zhuǎn)變都是通過(guò)轉(zhuǎn)錄因子調(diào)控。目前研究發(fā)現(xiàn)超級(jí)增強(qiáng)子調(diào)控的轉(zhuǎn)錄依賴于BRD4、Mediator復(fù)合體、包含細(xì)胞周期素依賴性激酶7 (cyclin-dependent kinase 7, CDK7)的TF ⅡH復(fù)合體和包含CDK9的轉(zhuǎn)錄延伸復(fù)合體(P-TEFb)[39]。CDK7對(duì)Pol Ⅱ C末端區(qū)域(C terminal domain，CTD)第5位絲氨酸磷酸化起始轉(zhuǎn)錄[47]；CDK9主要對(duì)Pol Ⅱ CTD 第2位絲氨酸磷酸化促進(jìn)轉(zhuǎn)錄暫停的Pol Ⅱ進(jìn)入轉(zhuǎn)錄延伸階段，也稱作Pol Ⅱ的釋放[39]。另外，BRD4通過(guò)招募Mediator復(fù)合體促進(jìn)超級(jí)增強(qiáng)子的裝配進(jìn)而促進(jìn)暫停狀態(tài)的Pol II的釋放[48]。CDK12/13可以加速Pol Ⅱ的轉(zhuǎn)錄延伸[49,50]。因此，目前普遍認(rèn)為超級(jí)增強(qiáng)子調(diào)控轉(zhuǎn)錄的關(guān)鍵調(diào)節(jié)點(diǎn)Mediator復(fù)合體、BRD4和關(guān)鍵的CDK有利于開(kāi)發(fā)成治療腫瘤的新靶點(diǎn)[6]。基于上述的轉(zhuǎn)錄抑制的關(guān)鍵節(jié)點(diǎn)，目前對(duì)于超級(jí)增強(qiáng)子這一靶點(diǎn)的藥物主要有以下幾類：(1) 針對(duì)BRD家族蛋白的抑制劑或者降解劑；(2) CDK7抑制劑；(3) 其他類型抑制劑(表1)。

表1 在腫瘤治療中以超級(jí)增強(qiáng)子為靶點(diǎn)的小分子抑制劑研究現(xiàn)狀

“-”代表未進(jìn)入臨床試驗(yàn)。

JQ1通過(guò)與BRD4的bromodomain結(jié)構(gòu)域結(jié) 合而抑制BRD4與發(fā)生乙?；揎椀牡鞍紫嗷プ饔肹59,60]，也就限制了BRD4和超級(jí)增強(qiáng)子的H3K27ac位點(diǎn)結(jié)合，抑制超級(jí)增強(qiáng)子和啟動(dòng)子的相互作用，進(jìn)而影響癌基因的轉(zhuǎn)錄[17]。由于超級(jí)增強(qiáng)子所調(diào)控的轉(zhuǎn)錄對(duì)于轉(zhuǎn)錄因子的濃度變化特別敏感，JQ1處理可以優(yōu)先阻止BRD4和超級(jí)增強(qiáng)子上的乙?；揎椢稽c(diǎn)結(jié)合，進(jìn)而特異性的抑制超級(jí)增強(qiáng)子介導(dǎo)的轉(zhuǎn)錄激活[9,17]。除此之外，還發(fā)現(xiàn)BRD抑制劑iBET762、OTX015、CPI0610和iBET151等，前3者已經(jīng)進(jìn)入臨床實(shí)驗(yàn)階段[22,51,61]。dBET系列化合物是基于JQ1的化學(xué)結(jié)構(gòu)研發(fā)的特異性更高的BRD4抑制劑，其可以特異性的介導(dǎo)BRD家族蛋白的降解[62]，從而阻止BRD家族蛋白識(shí)別超級(jí)增強(qiáng)子的乙?；稽c(diǎn)，影響超級(jí)增強(qiáng)子活性，抑制轉(zhuǎn)錄[63]。研究表明，BETd- 246可以靶向特異的降解BRD家族蛋白，相對(duì)于iBET- 211在三陰性乳腺癌中也表現(xiàn)出更好的治療效果[52]。

THZ1是CDK7特異的抑制劑，依賴于超級(jí)增強(qiáng)子介導(dǎo)的腫瘤細(xì)胞對(duì)于THZ1高度敏感[64]。THZ1可以和CDK7的第312位半胱氨酸共價(jià)結(jié)合，抑制CDK7的激酶活性，從而抑制CDK7對(duì)于Pol Ⅱ CTD的第五位絲氨酸磷酸化，抑制轉(zhuǎn)錄起始，進(jìn)一步阻止Pol Ⅱ在啟動(dòng)子近端暫停。超級(jí)增強(qiáng)子主要調(diào)控暫停的Pol Ⅱ釋放，THZ1處理之后在啟動(dòng)子近端的Pol Ⅱ減少，也減少在增強(qiáng)子處的Pol Ⅱ結(jié)合，最終抑制轉(zhuǎn)錄[55,64]。THZ1處理之后超級(jí)增強(qiáng)子活性下降，導(dǎo)致多種癌基因轉(zhuǎn)錄抑制，從而抑制多種腫瘤細(xì)胞的生長(zhǎng)和增殖[64]。SY-1365是Syros公司研發(fā)的CDK7的特異性抑制劑，可以選擇性抑制多種實(shí)體瘤(乳腺癌、卵巢癌和小細(xì)胞肺癌等)和血癌(急性髓細(xì)胞樣白血病和急性淋巴細(xì)胞白血病)，目前對(duì)于晚期實(shí)體瘤的實(shí)驗(yàn)處于一期臨床階段。該公司通過(guò)對(duì)腫瘤細(xì)胞的基因檢測(cè)分析，發(fā)現(xiàn)急性髓細(xì)胞白血病病人和骨髓增生異常綜合征病人具有受超級(jí)增強(qiáng)子調(diào)控的RARA和IRF8基因的高表達(dá)，并且發(fā)現(xiàn)SY- 1425可以作用于維甲酸受體α(RARα)，在臨床上對(duì)上述兩類病人具有較好的治療效果。

CDK12是調(diào)節(jié)轉(zhuǎn)錄延伸的一個(gè)激酶，在T細(xì)胞白血病中THZ531可以特異性抑制CDK12/13，有效抑制超級(jí)增強(qiáng)子介導(dǎo)的基因表達(dá)[57]。在急性髓性白血病中抑制Mediator激酶(CDK8/19)活性可以上調(diào)腫瘤抑制因子相關(guān)的超級(jí)增強(qiáng)子活性，激活腫瘤抑制基因的表達(dá)，最終達(dá)到抗白血病的活性[22]。類似的，CDK4/6抑制劑LEE011選擇性抑制CDK4，下調(diào)cyclin D1相關(guān)的超級(jí)增強(qiáng)子活性，有效的促進(jìn)尤因肉瘤細(xì)胞的凋亡[58]。

4 結(jié)語(yǔ)與展望

目前關(guān)于超級(jí)增強(qiáng)子的研究，發(fā)現(xiàn)超級(jí)增強(qiáng)子在多種腫瘤細(xì)胞中均有激活，而激活的這些超級(jí)增強(qiáng)子往往促進(jìn)癌基因的產(chǎn)生，維持癌細(xì)胞特性。通過(guò)抑制CDK、BRD4和Mediator復(fù)合體均可以干擾超級(jí)增強(qiáng)子的活性。超級(jí)增強(qiáng)子的先驅(qū)者Young R.A.與JQ1/iBET研發(fā)者Bradner J.E.這兩位科學(xué)家曾預(yù)言超級(jí)增強(qiáng)子具有廣闊的研發(fā)前景和價(jià)值，必將成為下一個(gè)藥物研發(fā)的黃金靶點(diǎn)，因?yàn)獒槍?duì)這一靶點(diǎn)有望開(kāi)發(fā)一種精確影響基因調(diào)控元件的藥物，為此這兩位科學(xué)家聯(lián)手成立Syros公司專門(mén)研發(fā)針對(duì)超級(jí)增強(qiáng)子這一靶點(diǎn)的抗癌藥。但是到目前為止對(duì)于超級(jí)增強(qiáng)子各個(gè)組分的研究還有欠缺：在癌細(xì)胞中組成超級(jí)增強(qiáng)子的每個(gè)增強(qiáng)子的活性是否和正常細(xì)胞中對(duì)應(yīng)的增強(qiáng)子活性一致？信號(hào)通路活性的改變是怎樣影響單個(gè)增強(qiáng)子組裝成超級(jí)增強(qiáng)子的？從治療角度考慮，也需要探索清楚超級(jí)增強(qiáng)子各個(gè)組分之間是怎么發(fā)揮作用的，藥物是怎樣抑制超級(jí)增強(qiáng)子各組分的活性。

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Research progress of super enhancer in cancer

Zhiqiang Wu1,2, Zeyun Mi3

Super enhancers (SEs) are composed of clusters of enhancers in close genomic proximity. They constitute a large family of regulatory elements that specify gene expression patterns and cell identity. SE regions consist of unusually strong enrichment of binding sites for transcriptional factors, cofactors, and enhancers associated with epigenetic modifications. SEs play important roles in regulating the aberrant gene expression in tumor cells.SEs, cancer cells activate the expression of various oncogenes, and promote cell proliferation, invasion and migration properties. Hence suppression of SEs activities could inhibit the growth and survival of cancer cells. In this review, we summarize the fundamental principles, functions and regulation of super enhancers and therapeutic potential in targeting SEs in cancer cells, thereby introducing and providing new conceptions for development of antineoplastic drugs.

enhancer; super enhancer; transcription; cancer

2018-07-13;

2018-09-21

國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：81502660，31700144)和天津市自然科學(xué)基金項(xiàng)目(編號(hào)：16JCQNJC10000, 17JCQNJC10600)資助[Supported by the National Natural Science Foundation of China (Nos. 81502660，31700144) and Tianjin Municipal Science and Technology Commission (Nos. 16JCQNJC10000, 17JCQNJC10600)]

吳志強(qiáng)，博士，講師，研究方向：放射生物學(xué)，腫瘤分子生物學(xué)。E-mail: zwu08@tmu.edu.cn

米澤云，博士，講師，研究方向：腫瘤分子生物學(xué)。E-mail: mizeyun@tmu.edu.cn

10.16288/j.yczz.18-152

2018/11/6 17:30:31

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20181106.1730.003.html

(責(zé)任編委: 方向東)