Department of Medicine, Università degli Studi di Udine, Institute for Biomedicine, P.le Kolbe 4, Udine 33100, Italy.
Eurac Research, Institute for Biomedicine, Via Alessandro Volta 21, Bolzano 39100, Italy.
Biomed Pharmacother. 2024 Apr;173:116374. doi: 10.1016/j.biopha.2024.116374. Epub 2024 Mar 5.
Here we present the generation and characterization of patient-derived organoids (PDOs) from colorectal cancer patients. PDOs derived from two patients with TP53 mutations were tested with two different HDAC inhibitors (SAHA and NKL54). Cell death induction, transcriptome, and chromatin accessibility changes were analyzed. HDACIs promote the upregulation of low expressed genes and the downregulation of highly expressed genes. A similar differential effect is observed at the level of chromatin accessibility. Only SAHA is a potent inducer of cell death, which is characterized by the upregulation of BH3-only genes BIK and BMF. Up-regulation of BIK is associated with increased accessibility in an intronic region that has enhancer properties. SAHA, but not NKL54, also causes downregulation of BCL2L1 and decreases chromatin accessibility in three distinct regions of the BCL2L1 locus. Both inhibitors upregulate the expression of innate immunity genes and members of the MHC family. In summary, our exploratory study indicates a mechanism of action for SAHA and demonstrate the low efficacy of NKL54 as a single agent for apoptosis induction, using two PDOs. These observations need to be validated in a larger cohort of PDOs.
在这里，我们介绍了从结直肠癌患者中生成和表征的类器官（PDO）。对来自两名 TP53 基因突变患者的 PDO 进行了两种不同的 HDAC 抑制剂（SAHA 和 NKL54）的测试。分析了细胞死亡诱导、转录组和染色质可及性变化。HDACIs 促进低表达基因的上调和高表达基因的下调。在染色质可及性水平上也观察到类似的差异效应。只有 SAHA 是一种有效的细胞死亡诱导剂，其特征是 BH3 仅基因 BIK 和 BMF 的上调。BIK 的上调与具有增强子特性的内含子区域的可及性增加有关。SAHA 而非 NKL54 还导致 BCL2L1 的下调，并降低 BCL2L1 基因座三个不同区域的染色质可及性。两种抑制剂都上调了先天免疫基因和 MHC 家族成员的表达。总之，我们的探索性研究表明了 SAHA 的作用机制，并证明了 NKL54 作为单一药物诱导细胞凋亡的低疗效，使用了两种 PDO。这些观察结果需要在更大的 PDO 队列中进行验证。
