Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China.
Hepatology. 2023 Nov 1;78(5):1384-1401. doi: 10.1097/HEP.0000000000000268. Epub 2023 Jan 13.
HCC is a highly heterogeneous disease that is caused largely by genomic copy number variations. Herein, the mechanistic and therapeutically targeted role of vacuolar protein sorting 72 homologue (VPS72), a novel copy number variation cis-driven gained gene identified by genome-wide copy number variation and transcriptome analyses in HCC, is not well understood.
First, overexpression of VPS72 enhanced the initiation and progression of HCC in vitro and in vivo . Mechanistically, VPS72 interacted with the oncoproteins MYC and actin-like 6A (ACTL6A) and promoted the formation of the ACTL6A/MYC complex. Furthermore, ACTL6A regulated VPS72 protein stability by weakening the interaction between tripartite motif containing 21 (TRIM21) and VPS72. Thus, the interaction between VPS72 and ACTL6A enhanced the affinity of MYC for its target gene promoters and promoted their transcription, thereby contributing to HCC progression, which was inhibited by adeno-associated virus serotype 8 (AAV8)-mediated short hairpin RNA (shRNA) against VPS72.
This study reveals the molecular mechanism of ACTL6A/VPS72/MYC in HCC, providing a theoretical basis and therapeutic target for this malignancy.
肝细胞癌（HCC）是一种高度异质性疾病，主要由基因组拷贝数变异引起。在此，通过全基因组拷贝数变异和转录组分析，发现液泡蛋白分选 72 同源物（VPS72）是一种新型拷贝数变异顺式驱动获得基因，其在 HCC 中的机制和治疗靶向作用尚不清楚。
首先，过表达 VPS72 增强了 HCC 的体外和体内起始和进展。从机制上讲，VPS72 与癌蛋白 MYC 和肌动蛋白样 6A（ACTL6A）相互作用，并促进 ACTL6A/MYC 复合物的形成。此外，ACTL6A 通过削弱三肽基含 21 （TRIM21）和 VPS72 之间的相互作用来调节 VPS72 蛋白稳定性。因此，VPS72 和 ACTL6A 之间的相互作用增强了 MYC 与其靶基因启动子的亲和力，并促进了它们的转录，从而促进 HCC 的进展，而 AAV8 介导的短发夹 RNA（shRNA）针对 VPS72 则抑制了这一过程。
本研究揭示了 ACTL6A/VPS72/MYC 在 HCC 中的分子机制，为该恶性肿瘤提供了理论基础和治疗靶点。
