Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-79, New Orleans, LA, 70112, USA.
J Exp Clin Cancer Res. 2024 Apr 19;43(1):117. doi: 10.1186/s13046-024-03036-5.
Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tract with poor prognosis. Further mechanistic insights into the molecular mechanisms of CCA are needed to develop more effective target therapy.
The expression of the histone lysine acetyltransferase KAT2B in human CCA was analyzed in human CCA tissues. CCA xenograft was developed by inoculation of human CCA cells with or without KAT2B overexpression into SCID mice. Western blotting, ChIP-qPCR, qRT-PCR, protein immunoprecipitation, GST pull-down and RNA-seq were performed to delineate KAT2B mechanisms of action in CCA.
We identified KAT2B as a frequently downregulated histone acetyltransferase in human CCA. Downregulation of KAT2B was significantly associated with CCA disease progression and poor prognosis of CCA patients. The reduction of KAT2B expression in human CCA was attributed to gene copy number loss. In experimental systems, we demonstrated that overexpression of KAT2B suppressed CCA cell proliferation and colony formation in vitro and inhibits CCA growth in mice. Mechanistically, forced overexpression of KAT2B enhanced the expression of the tumor suppressor gene NF2, which is independent of its histone acetyltransferase activity. We showed that KAT2B was recruited to the promoter region of the NF2 gene via interaction with the transcription factor SP1, which led to enhanced transcription of the NF2 gene. KAT2B-induced NF2 resulted in subsequent inhibition of YAP activity, as reflected by reduced nuclear accumulation of oncogenic YAP and inhibition of YAP downstream genes. Depletion of NF2 was able to reverse KAT2B-induced reduction of nuclear YAP and subvert KAT2B-induced inhibition of CCA cell growth.
This study provides the first evidence for an important tumor inhibitory effect of KAT2B in CCA through regulation of NF2-YAP signaling and suggests that this signaling cascade may be therapeutically targeted for CCA treatment.
胆管癌（CCA）是一种恶性程度很高的胆道恶性肿瘤，预后较差。为了开发更有效的靶向治疗方法，需要进一步深入了解 CCA 的分子机制。
分析了人 CCA 组织中组蛋白赖氨酸乙酰转移酶 KAT2B 的表达。将过表达 KAT2B 的人 CCA 细胞接种到 SCID 小鼠中，建立 CCA 异种移植模型。采用 Western blot、ChIP-qPCR、qRT-PCR、蛋白免疫沉淀、GST 下拉和 RNA-seq 等方法研究 KAT2B 在 CCA 中的作用机制。
我们发现 KAT2B 是人 CCA 中经常下调的组蛋白乙酰转移酶。KAT2B 的下调与 CCA 疾病进展和 CCA 患者的预后不良显著相关。人 CCA 中 KAT2B 表达的减少归因于基因拷贝数缺失。在实验系统中，我们证明过表达 KAT2B 可抑制体外 CCA 细胞增殖和集落形成，并抑制小鼠体内 CCA 的生长。机制上，强制过表达 KAT2B 增强了肿瘤抑制基因 NF2 的表达，这与它的组蛋白乙酰转移酶活性无关。我们发现 KAT2B 通过与转录因子 SP1 相互作用被募集到 NF2 基因的启动子区域，从而导致 NF2 基因的转录增强。KAT2B 诱导的 NF2 导致随后的 YAP 活性抑制，表现为致癌 YAP 的核积累减少和 YAP 下游基因的抑制。NF2 的耗竭能够逆转 KAT2B 诱导的核 YAP 减少，并颠覆 KAT2B 诱导的 CCA 细胞生长抑制。
本研究首次证明了 KAT2B 通过调节 NF2-YAP 信号在 CCA 中具有重要的肿瘤抑制作用，并表明该信号级联可能是 CCA 治疗的治疗靶点。
