ARID1A 介导的组蛋白H2B单泛素化修饰在抑制胰腺癌转移中的表观遗传机制

ARID1A, a subunit of SWI/SNF, plays crucial functions in suppressing cancer metastasis, while mutated in approximately 15% of pancreatic cancers. However, the mechanism by which this alteration drives tumor metastasis remains poorly understood. Our preliminary studies found that the function of ARID1A in suppressing pancreatic cancer metastasis was specifically depend on the BC box in its C-terminal domain. Upon BC box, ARID1A potentially activated as E3 ubiquitin ligase targeting H2B. Given H2Bub1 plays essential role on suppressing tumor metastasis by mechanism of facilitating the transcriptional elongation of tumor suppressors via controlling the broad H3K4me3 width. In current proposal, we aim to identify a novel mechanism in which ARID1A functions as E3 ubiquitin ligase of H2B to control pancreatic cancer metastasis, it would help us to find potential therapeutic strategy in pancreatic cancer.

胰腺癌被称为“万癌之王”，是5年生存率最低的癌症，预计未来20年我国胰腺癌确诊患者将增加2倍。ARID1A是最近发现在胰腺癌中突变率前五的基因。ARID1A频繁发生截短突变或者错义突变，导致C-末端结构域功能缺失。然而ARID1A及其C-端结构域在胰腺癌中的生物学功能目前还不明了。我们前期结果表明，ARID1A具有抑制胰腺癌细胞迁移的功能，并且这功能依赖于C-端结构域的BC box模体，随后我们证实ARID1A具有潜在的驱动组蛋白H2B单泛素化（H2Bub1）的泛素连接酶功能，而这一功能依赖于BC模体。因此，我们将采用高通量测序技术（mRNA-seq、ChIP-seq），从体外和体内深入研究ARID1A潜在的泛素连接酶活性在调控胰腺癌转移中的作用机制。该研究将会为制定ARID1A缺失的胰腺癌治疗方案提供理论依据，并有机会找到潜在的治疗靶标。

胰腺癌被称为“万癌之王”，是5年生存率最低的癌症。20%以上的人类癌症中BAF染色质重塑复合物都发生了突变，其成员ARID1A在胰腺癌中突变率最高，达到10%左右。然而，ARID1A在胰腺癌中作用还知之甚少。在该项目中，我们采用CRISPR/Cas9基因编辑工具构建了ARID1A缺失和不同结构域突变ARID1A的PANC1细胞株。然后通过ChIP-seq和RNA-seq分析，发现了一条ARID1A促进胰腺癌抑癌基因表达的全新表观遗传路径：ARID1A通过CBRB结构域与RNF40相互作用介导H2Bub1，进而促进H3K4me3向转录起始位点下游延伸，然后提高基因转录延伸。此外，我们通过分析内源性ARID1A的截断突变产生的不同mRNA异构体，我发现截断突变导致的CBRB缺失的ARID1A异构体具有促进癌症发生的作用。该研究发现了CBRB截断突变的ARID1A异构体是潜在的胰腺癌治疗靶位点。