Department of Chemistry, Wayne State University, Detroit, MI, USA.
Mol Omics. 2021 Aug 9;17(4):544-553. doi: 10.1039/d0mo00047g.
Histone deacetylase (HDAC) proteins, which regulate the acetylation state of proteins, are the targets of multiple clinical drugs for cancer treatment. Due to the heterogeneity of tumors, HDAC proteins play different roles in the progression of various cancer types. For example, MDA-MB-468 and MDA-MB-231 cells are both triple negative breast cancer cells but belong to different subtypes that display different response to HDAC inhibitor drugs. To investigate the role of HDAC proteins in breast cancer, the substrate and associated proteins of HDAC1 in MDA-MB-231, MDA-MB-468, and a normal breast epithelial cell line, MCF10A, were analyzed using substrate trapping mutants and proteomics-based mass spectrometry. All three cell lines demonstrated nonoverlapping substrate protein profiles. While both normal MCF10A and cancerous MDA-MB-468 cell lines contained similar HDAC1 associated proteins, including proteins associated with epigenetic and RNA processing mechanisms, the HDAC1 associated protein profile of MDA-MB-231 cells was devoid of expected epigenetic proteins. The variable associated protein profiles of MDA-MB-231 and MDA-MB-468 suggest that HDAC1 plays distinct roles in breast cancer cell biology, which might affect cancer aggressiveness and HDAC inhibitor sensitivity.
组蛋白去乙酰化酶（HDAC）蛋白调节蛋白质的乙酰化状态，是多种癌症治疗临床药物的作用靶点。由于肿瘤的异质性，HDAC 蛋白在各种癌症类型的进展中发挥不同的作用。例如，MDA-MB-468 和 MDA-MB-231 细胞均为三阴性乳腺癌细胞，但属于不同亚型，对 HDAC 抑制剂药物的反应不同。为了研究 HDAC 蛋白在乳腺癌中的作用，使用底物捕获突变体和基于蛋白质组学的质谱法分析了 MDA-MB-231、MDA-MB-468 和正常乳腺上皮细胞系 MCF10A 中 HDAC1 的底物和相关蛋白。这三种细胞系均表现出非重叠的底物蛋白谱。虽然正常 MCF10A 和癌性 MDA-MB-468 细胞系均含有相似的 HDAC1 相关蛋白，包括与表观遗传和 RNA 处理机制相关的蛋白，但 MDA-MB-231 细胞系的 HDAC1 相关蛋白谱缺乏预期的表观遗传蛋白。MDA-MB-231 和 MDA-MB-468 的可变相关蛋白谱表明，HDAC1 在乳腺癌细胞生物学中发挥独特的作用，这可能影响癌症的侵袭性和 HDAC 抑制剂的敏感性。
