南开大学教授叶丽虹等合作，近期取得重要工作进展。他们研究提出，HBXIP通过WTAP介导的m⁶A修饰和CEBPA激活的转录诱导PARP1在顺铂抗性肝癌中发挥作用。相关研究成果2024年6月13日在线发表于《中国药理学报》杂志上。

据介绍，聚ADP核糖聚合酶1（PARP1）是一种DNA结合蛋白，参与多种生物学功能，包括DNA损伤修复和转录调控。它在顺铂耐药性中起着至关重要的作用。然而，PARP1的确切调控途径尚未完全阐明。

研究人员表明，乙型肝炎X相互作用蛋白（HBXIP）可能对PARP1发挥调节控制作用。HBXIP作为一种转录共激活因子发挥作用，在临床环境中从肝癌患者获得的组织中与PARP1的表达呈正相关，其高表达促进了肝癌中的顺铂耐药性。研究人员发现，癌基因HBXIP通过上调RNA甲基转移酶WTAP来增加PARP1 m⁶A修饰的水平，从而导致PARP1蛋白的积累。

在这个过程中，一方面，HBXIP联合激活转录因子ETV5，促进WTAP启动子的激活，进一步促进WTAP甲基转移酶对PARP1的m⁶A修饰，增强PARP1的RNA稳定性。另一方面，HBXIP还可以联合激活转录因子CEBPA，增强PARP1启动子的活性，并促进PARP1表达的上调，最终增强DNA损伤修复能力，促进肝癌对顺铂的耐药性。值得注意的是，阿司匹林抑制HBXIP，从而降低PARP1的表达。

总之，这一研究揭示了一种增加PARP1丰度的新机制，阿司匹林治疗可以克服肝癌中的顺铂耐药性。

附：英文原文

Title: HBXIP induces PARP1 via WTAP-mediated m6A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma

Author: Fu, Xue-li, Guo, Shi-man, Ma, Jia-qi, Ma, Fang-yuan, Wang, Xue, Tang, Yan-xin, Li, Ye, Zhang, Wei-ying, Ye, Li-hong

Issue&Volume: 2024-06-13

Abstract: Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma.

DOI: 10.1038/s41401-024-01309-5

Source: https://www.nature.com/articles/s41401-024-01309-5