Zhang Cong, Zhu Jinmin, Lin Huaisong, Zhang Zhishuai, Kang Baoqiang, Li Fei, Shan Yongli, Zhang Yanqi, Xing Qi, Gu Jiaming, Hu Xing, Cui Yuanbin, Huang Jingxi, Zhou Tiancheng, Mai Yuchan, Chen Qianyu, Mao Rui, Li Peng, Pan Guangjin
Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou, 511436, China.
Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Development and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
Cell Oncol (Dordr). 2025 Apr 14. doi: 10.1007/s13402-025-01055-8.
Epithelial-mesenchymal transition (EMT) plays critical roles in tumor progress and treatment resistance of ovarian cancer (OC), resulting in the most deadly gynecological cancer in women. However, the cell-intrinsic mechanism underlying EMT in OC remains less illuminated.
SKOV3, the OC cell line, was treated with TGF-β to induce EMT or with SB431542, an inhibitor of the TGF-β signaling pathway, to reduce migration. The function of HBO1 in EMT was confirmed by knock-down or overexpression of HBO1 in SKOV3 cells. The role of HBO1 in cell proliferation and apoptosis of SKOV3 cells was analyzed by flow cytometry. The whole-genome transcriptome was used to compare significantly different genes in control and HBO1-KD SKOV3 cells. T-cell cytotoxicity assays were measured by an IVIS spectrum. The chromatin binding of HBO1 was investigated using CUT&Tag-seq.
Here, we show that HBO1, a MYST histone acetyltransferase (HAT), is a cell-intrinsic determinant for EMT in OC cells. HBO1 is greatly elevated during TGF-β-triggered EMT in SKOV3 OC cells as well as in later stages of clinical OC samples. HBO1 Knock-down (KD) in SKOV3 cells blocks TGF-β-triggered EMT, migration, invasion and tumor formation in vivo. Interestingly, HBO1 KD in SKOV3 cells suppresses their resistance to CAR-T cells. Mechanistically, HBO1 co-binds the gene sets responsible for EMT with SMAD4 and orchestrates a gene regulatory network critical for tumor progression in SKOV3 cells.
HBO1 plays an essential onco-factor to drive EMT and promote the immunotherapy resistance in ovarian cancer cells. Together, we reveal a critical role of HBO1 mediated epigenetic mechanism in OC progression, providing an insight into designing new therapy strategies.
上皮-间质转化（EMT）在卵巢癌（OC）的肿瘤进展和治疗耐药中起关键作用，卵巢癌是女性最致命的妇科癌症。然而，OC中EMT的细胞内在机制仍不太清楚。
使用OC细胞系SKOV3，用转化生长因子-β（TGF-β）处理以诱导EMT，或用TGF-β信号通路抑制剂SB431542处理以减少迁移。通过在SKOV3细胞中敲低或过表达HBO1来证实HBO1在EMT中的功能。通过流式细胞术分析HBO1在SKOV3细胞增殖和凋亡中的作用。使用全基因组转录组比较对照和HBO1敲低（KD）的SKOV3细胞中显著不同的基因。通过IVIS光谱仪测量T细胞细胞毒性测定。使用CUT&Tag-seq研究HBO1的染色质结合。
在此，我们表明HBO1是一种MYST组蛋白乙酰转移酶（HAT），是OC细胞中EMT的细胞内在决定因素。在SKOV3 OC细胞中TGF-β触发的EMT期间以及临床OC样本的后期阶段，HBO1显著升高。SKOV3细胞中的HBO1敲低（KD）可阻断TGF-β触发的EMT、迁移、侵袭和体内肿瘤形成。有趣的是，SKOV3细胞中的HBO1 KD抑制了它们对嵌合抗原受体T细胞（CAR-T细胞）的抗性。机制上，HBO1与SMAD4共同结合负责EMT的基因集，并协调对SKOV3细胞肿瘤进展至关重要的基因调控网络。
HBO1是驱动EMT并促进卵巢癌细胞免疫治疗耐药性的重要致癌因子。总之，我们揭示了HBO1介导的表观遗传机制在OC进展中的关键作用，为设计新的治疗策略提供了见解。
