Sun Yanmei, Xu Mingjing, Wan Ho Lee, Ding Xiaofan, Wong Alissa M, Pu Dandan, Ng Kelvin K, Wong Nathalie
Department of Surgery, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao, China.
J Hepatol. 2025 Jul;83(1):92-104. doi: 10.1016/j.jhep.2024.12.037. Epub 2025 Jan 7.
BACKGROUND & AIMS: The ubiquitin receptor ADRM1/Rpn13 governs the specificity of eukaryotic protein degradation. We first discovered a novel spliced variant of ADRM1 with a skipped exon 9, termed ADRM1-ΔEx9, in human hepatocellular carcinoma (HCC) by SMRT sequencing. The aim of this study was to elucidate this novel ubiquitin receptor's underlying biology and clinical implications in HCC.
The role of ADRM1-ΔEx9 in early liver carcinogenesis was studied using human liver-derived non-tumoral organoids and a murine model with hydrodynamic in vivo transfection. ADRM1-ΔEx9 biology in HCC and its potential as a biomarker for predicting olaparib response were investigated using patient-derived tumor organoids and xenograft models. The underlying mechanism was delineated using the Proteome Profiler Human Ubiquitin Array.
ADRM1-ΔEx9, not its full-length counterpart, conferred human liver organoids with pro-survival advantages and led to more profound tumor formation in a hydrodynamic transfected murine model. Functional knockdown resulted in spontaneous apoptosis in cell lines and patient-derived organoids, highlighting a pivotal role for ADRM1-ΔEx9 in HCC oncogenicity. Mechanistically, the shortened C-terminus of ADRM1-ΔEx9 interacted with a different deubiquitinase partner (BAP1) to alter proteasome specificity. The new exon 8-10 fusion in ADRM1-ΔEx9 creates a de novo binding site for the tumor suppressor protein FBXW7, resulting in its selective proteasome-mediated degradation. The loss of FBXW7 protein in ADRM1-ΔEx9-expressing tumors underscores their sensitivity to the PARP inhibitor olaparib. Notably, findings on ADRM1-ΔEx9 in primary HCC tumors denote its overexpression in a subgroup of patients with inferior survival and a window of therapeutic opportunity through a synthetic lethal association with olaparib.
ADRM1-ΔEx9 redirects ubiquitin proteasome specificity to selectively degrade the tumor suppressor protein FBXW7. This promotes HCC tumor formation and provides a synthetic lethal link for PARP inhibitor therapy.
Reduced tumor suppressor protein FBXW7 expression is pivotal in hepatocellular carcinoma (HCC) pathogenesis and other liver diseases. However, the regulatory mechanism governing FBXW7 protein expression remains elusive. Herein, we unveil a non-canonical spliced isoform of the ubiquitin receptor ADRM1 that selectively degrades FBXW7 protein, thereby promoting the premalignant transformation of hepatic cells and conferring growth advantages to HCC tumors. Furthermore, our results demonstrate that ADRM1-ΔEx9-expressing HCC tumors exhibited sensitivity to olaparib in a dose-dependent manner, implicating the potential use of olaparib in targeting ADRM1-ΔEx9-driven HCC growth.
泛素受体ADRM1/Rpn13决定真核生物蛋白质降解的特异性。我们首次通过单分子实时测序在人类肝细胞癌（HCC）中发现了一种新的ADRM1剪接变体，其外显子9缺失，命名为ADRM1-ΔEx9。本研究旨在阐明这种新型泛素受体在HCC中的潜在生物学特性及临床意义。
利用人肝脏来源的非肿瘤类器官和体内流体动力学转染的小鼠模型研究ADRM1-ΔEx9在早期肝癌发生中的作用。利用患者来源的肿瘤类器官和异种移植模型研究ADRM1-ΔEx9在HCC中的生物学特性及其作为预测奥拉帕尼反应生物标志物的潜力。使用蛋白质组分析人类泛素阵列来阐明其潜在机制。
ADRM1-ΔEx9而非其全长对应物赋予人类肝脏类器官生存优势，并在流体动力学转染的小鼠模型中导致更严重的肿瘤形成。功能敲低导致细胞系和患者来源的类器官自发凋亡，突出了ADRM1-ΔEx9在HCC致癌性中的关键作用。从机制上讲，ADRM1-ΔEx9缩短的C末端与不同的去泛素化酶伴侣（BAP1）相互作用，改变蛋白酶体特异性。ADRM1-ΔEx9中新的外显子8-10融合为肿瘤抑制蛋白FBXW7创造了一个新的结合位点，导致其被蛋白酶体选择性降解。在表达ADRM1-ΔEx9的肿瘤中FBXW7蛋白的缺失强调了它们对PARP抑制剂奥拉帕尼的敏感性。值得注意的是，原发性HCC肿瘤中关于ADRM1-ΔEx9的研究结果表明，它在生存期较差的患者亚组中过表达，并通过与奥拉帕尼的合成致死关联提供了一个治疗机会窗口。
ADRM1-ΔEx9重定向泛素蛋白酶体特异性以选择性降解肿瘤抑制蛋白FBXW7。这促进了HCC肿瘤形成，并为PARP抑制剂治疗提供了合成致死联系。
肿瘤抑制蛋白FBXW7表达降低在肝细胞癌（HCC）发病机制和其他肝脏疾病中起关键作用。然而，调控FBXW7蛋白表达的机制仍不清楚。在此，我们揭示了泛素受体ADRM1的一种非经典剪接异构体，它选择性降解FBXW7蛋白，从而促进肝细胞的癌前转化并赋予HCC肿瘤生长优势。此外，我们的结果表明，表达ADRM1-ΔEx9的HCC肿瘤对奥拉帕尼呈剂量依赖性敏感，这意味着奥拉帕尼在靶向ADRM1-ΔEx9驱动的HCC生长方面具有潜在用途。
