Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV 26505, USA.
Lane Department of Computer Science & Electrical Engineering, West Virginia University, Morgantown, WV 26506, USA.
Int J Mol Sci. 2024 Aug 20;25(16):9022. doi: 10.3390/ijms25169022.
Multiple myeloma is the second most hematological cancer. RUVBL1 and RUVBL2 form a subcomplex of many chromatin remodeling complexes implicated in cancer progression. As an inhibitor specific to the RUVBL1/2 complex, CB-6644 exhibits remarkable anti-tumor activity in xenograft models of Burkitt's lymphoma and multiple myeloma (MM). In this work, we defined transcriptional signatures corresponding to CB-6644 treatment in MM cells and determined underlying epigenetic changes in terms of chromatin accessibility. CB-6644 upregulated biological processes related to interferon response and downregulated those linked to cell proliferation in MM cells. Transcriptional regulator inference identified E2Fs as regulators for downregulated genes and MED1 and MYC as regulators for upregulated genes. CB-6644-induced changes in chromatin accessibility occurred mostly in non-promoter regions. Footprinting analysis identified transcription factors implied in modulating chromatin accessibility in response to CB-6644 treatment, including ATF4/CEBP and IRF4. Lastly, integrative analysis of transcription responses to various chemical compounds of the molecular signature genes from public gene expression data identified CB-5083, a p97 inhibitor, as a synergistic candidate with CB-6644 in MM cells, but experimental validation refuted this hypothesis.
多发性骨髓瘤是第二大血液系统癌症。RUVBL1 和 RUVBL2 形成许多染色质重塑复合物的亚复合物，这些复合物与癌症进展有关。作为 RUVBL1/2 复合物的特异性抑制剂，CB-6644 在伯基特淋巴瘤和多发性骨髓瘤（MM）的异种移植模型中表现出显著的抗肿瘤活性。在这项工作中，我们确定了 CB-6644 处理 MM 细胞时对应的转录特征，并根据染色质可及性确定了潜在的表观遗传变化。CB-6644 上调了与干扰素反应相关的生物学过程，下调了与 MM 细胞增殖相关的过程。转录调控因子推断确定 E2Fs 为下调基因的调控因子，MED1 和 MYC 为上调基因的调控因子。CB-6644 诱导的染色质可及性变化主要发生在非启动子区域。足迹分析确定了转录因子，这些转录因子在响应 CB-6644 处理时参与调节染色质可及性，包括 ATF4/CEBP 和 IRF4。最后，对来自公共基因表达数据的分子特征基因的各种化学化合物的转录反应进行综合分析，确定了 p97 抑制剂 CB-5083 是 MM 细胞中与 CB-6644 具有协同作用的候选药物，但实验验证否定了这一假设。
