Lv Jinjuan, Yu Xiaoqi, Liu Xiaoqian, Zhang Qianshi, Zhang Mengyan, Gao Jianfeng, Sun Zhiwei, Zhang Feifan, Zuo Yunfei, Ren Shuangyi
Department of Clinical Biochemistry, College of Laboratory Diagnostic Medicine, Dalian Medical University, Dalian, 116044, China.
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
J Exp Clin Cancer Res. 2025 Jul 15;44(1):205. doi: 10.1186/s13046-025-03461-0.
Liver metastasis is a common cause of death in patients with colorectal cancer (CRC); however, its molecular mechanism remains unclear. Here, we aimed to reveal the role of the lncRNA STEAP3-AS1 in regulating chromatin remodelling and histone lactylation and explore the mechanism by which the lncRNA STEAP3-AS1 promotes CRC liver metastasis. This study provide new research ideas and a theoretical basis for the clinical treatment of cancer.
In this study, we used CRC organoid and nude mouse liver metastasis models to analyse the effect of the lncRNA STEAP3-AS1 on CRC liver metastasis. ATAC-seq, RNA-seq, DRIP-seq and Western blotting were used to screen for the lncRNA STEAP3-AS1 downstream prometastatic molecule MMP9 and the chromatin remodelling factor BRG1. The protein interactions between BRG1, p300, and HDAC3 were evaluated by Co-IP. The the binding of BRG1, ERG, P300, and H3K18la to the MMP9 gene promoter was detected using ChIP-qPCR.
The lncRNA STEAP3-AS1 interacts with its parental gene, STEAP3, to form an R-loop on the key chromatin remodelling factor BRG1, regulating the expression of BRG1. Further evidence suggests that BRG1 forms a protein complex with the histone lactylation eraser HDAC3 and the writer P300 to regulate the expression of H3K18la. Moreover, the ATAC-seq analysis revealed that the lncRNA STEAP3-AS1 promotes the chromatin accessibility of MMP9, and a motif and database analysis identified the tumour metastasis factor ERG as an MMP9 transcription factor. The lncRNA STEAP3-AS1 mediates regulation of H3K18la activation of MMP9 by the BRG1/ERG/P300 complex.
In summary, these findings revealed that the lncRNA STEAP3-AS1 interacts with its parental gene STEAP3 to regulate H3K18la through BRG1, resulting in changes in chromatin accessibility, thereby driving ERG enrichment an the MMP9 promoter to activate MMP9 transcription and promote CRC liver metastasis. Our findings reveal a novel mechanism by which the lncRNA STEAP3-AS1 promotes CRC metastasis from an epigenetic perspective.
肝转移是结直肠癌（CRC）患者常见的死亡原因；然而，其分子机制仍不清楚。在此，我们旨在揭示长链非编码RNA STEAP3-AS1在调节染色质重塑和组蛋白乳酸化中的作用，并探索长链非编码RNA STEAP3-AS1促进CRC肝转移的机制。本研究为癌症的临床治疗提供了新的研究思路和理论依据。
在本研究中，我们使用CRC类器官和裸鼠肝转移模型来分析长链非编码RNA STEAP3-AS1对CRC肝转移的影响。采用ATAC-seq、RNA-seq、DRIP-seq和蛋白质免疫印迹法筛选长链非编码RNA STEAP3-AS1下游的促转移分子MMP9和染色质重塑因子BRG1。通过免疫共沉淀评估BRG1、p300和HDAC3之间的蛋白质相互作用。使用染色质免疫沉淀定量PCR（ChIP-qPCR）检测BRG1、ERG、P300和H3K18la与MMP9基因启动子的结合。
长链非编码RNA STEAP3-AS1与其亲本基因STEAP3相互作用，在关键染色质重塑因子BRG1上形成R环，调节BRG1的表达。进一步的证据表明，BRG1与组蛋白乳酸化擦除酶HDAC3和写入酶P300形成蛋白质复合物，以调节H3K18la的表达。此外，ATAC-seq分析表明，长链非编码RNA STEAP3-AS1促进MMP9的染色质可及性，基序和数据库分析确定肿瘤转移因子ERG为MMP9转录因子。长链非编码RNA STEAP3-AS1介导BRG1/ERG/P300复合物对MMP9的H3K18la激活的调控。
总之，这些发现表明，长链非编码RNA STEAP3-AS1与其亲本基因STEAP3相互作用，通过BRG1调节H3K18la，导致染色质可及性改变，从而驱动ERG在MMP9启动子上富集，激活MMP9转录并促进CRC肝转移。我们的发现从表观遗传学角度揭示了长链非编码RNA STEAP3-AS1促进CRC转移的新机制。
