Snail 基因转录启始区组蛋白H3K4修饰的变化在EMT中的作用及对前列腺癌转移的影响

有研究显示,EMT过程存在组蛋白修饰的变化,但该变化与EMT相关转录因子表达的关系尚不明确,我们前期结果显示:EMT重要转录因子Snail转录起始区(TSS)附近H3K4Me3的富集在TGFb诱导前列腺癌细胞EMT中发生显著变化,且与Snail表达相关; 进一步用RNAi 抑制COMPASS/-like复合体(催化H3K4Me3生成)中重要组份WDR5&RBBP5也能抑制Snail表达上调及EMT过程.另有研究报道,TGFb通路下游组份pSMAD2/3能调控Snail表达,SMAD2/3能否通过募集COMPASS/-like复合体促进H3K4Me3在Snail TSS富集,进而促进Snail表达和EMT？WDR5,RBBP5能否调控细胞对TGFb的敏感性? WDR5/RBBP5及EMT相关分子的表达与PC转移是否相关?我们将回答并阐明这些问题。以上假设如能证实,将为PC治疗提供新的靶点。

Alteration of whole genome histone modification occurred in EMT progress, however, relationship of EMT- associated transcription factors expression with histone modification remains elusive. Our results demonstrated H3K4Me3 enrichment changes notable around Snail Transcription Start Site, with the same tendency to Snail expression, during TGFb induced prostate cancer cell EMT. Knocking-down of WDR5 & RBBP5 - two crucial components of COMPASS/-like complex which catalyze H3K4Me3 formation, inhibited Snail expression and abrogated EMT progress. Previous studies show that phosphorylation of SAMD2/3 - a downstream effector of TGFb pathway regulated Snail transcription level, while is there possibility that SMAD2/3 promote H3K4Me3 at Snail TSS by recruiting COMPASS/-like complex? Does WDR5 & RBBP5 sensitize the susceptibility of prostate cancer cell to TGFb? Does WDR5/RBBP5 and EMT associated molecules expression positive correlated with tumor metastasis ？ If above hypothesis is correct, it will pave a way in solving of metastatic prostate cancer detection and treatment.