Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2022-05-24 , DOI: 10.1007/s10565-022-09731-3 Nicole Kiweler 1, 2 , Helena Schwarz 1 , Alexandra Nguyen 1 , Stephanie Matschos 3 , Christina Mullins 3 , Andrea Piée-Staffa 1 , Christina Brachetti 1 , Wynand P Roos 1 , Günter Schneider 4, 5 , Michael Linnebacher 3 , Walburgis Brenner 6 , Oliver H Krämer 1
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The epigenetic modifier histone deacetylase-2 (HDAC2) is frequently dysregulated in colon cancer cells. Microsatellite instability (MSI), an unfaithful replication of DNA at nucleotide repeats, occurs in about 15% of human colon tumors. MSI promotes a genetic frameshift and consequently a loss of HDAC2 in up to 43% of these tumors. We show that long-term and short-term cultures of colorectal cancers with MSI contain subpopulations of cells lacking HDAC2. These can be isolated as single cell-derived, proliferating populations. Xenografted patient-derived colon cancer tissues with MSI also show variable patterns of HDAC2 expression in mice. HDAC2-positive and HDAC2-negative RKO cells respond similarly to pharmacological inhibitors of the class I HDACs HDAC1/HDAC2/HDAC3. In contrast to this similarity, HDAC2-negative and HDAC2-positive RKO cells undergo differential cell cycle arrest and apoptosis induction in response to the frequently used chemotherapeutic 5-fluorouracil, which becomes incorporated into and damages RNA and DNA. 5-fluorouracil causes an enrichment of HDAC2-negative RKO cells in vitro and in a subset of primary colorectal tumors in mice. 5-fluorouracil induces the phosphorylation of KAP1, a target of the checkpoint kinase ataxia-telangiectasia mutated (ATM), stronger in HDAC2-negative cells than in their HDAC2-positive counterparts. Pharmacological inhibition of ATM sensitizes RKO cells to cytotoxic effects of 5-fluorouracil. These findings demonstrate that HDAC2 and ATM modulate the responses of colorectal cancer cells towards 5-FU.
Graphical abstract
中文翻译：
表观遗传修饰剂 HDAC2 和检查点激酶 ATM 决定微卫星不稳定结直肠癌细胞对 5-氟尿嘧啶的反应
表观遗传修饰剂组蛋白脱乙酰酶 2 (HDAC2) 在结肠癌细胞中经常失调。微卫星不稳定性 (MSI) 是一种 DNA 核苷酸重复的不忠实复制，大约 15% 的人类结肠肿瘤中出现这种情况。MSI 会促进遗传移码，从而导致高达 43% 的肿瘤中 HDAC2 缺失。我们发现，患有 MSI 的结直肠癌的长期和短期培养物含有缺乏 HDAC2 的细胞亚群。这些可以被分离为单细胞衍生的增殖群体。具有 MSI 的异种移植患者来源的结肠癌组织也在小鼠中显示出不同的 HDAC2 表达模式。HDAC2 阳性和 HDAC2 阴性 RKO 细胞对 I 类 HDAC HDAC1/HDAC2/HDAC3 的药理学抑制剂的反应相似。与这种相似性相反，HDAC2 阴性和 HDAC2 阳性 RKO 细胞响应常用化疗药物 5-氟尿嘧啶，经历不同的细胞周期停滞和细胞凋亡诱导，5-氟尿嘧啶掺入并损伤 RNA 和 DNA。5-氟尿嘧啶在体外和小鼠原发性结直肠肿瘤的子集中引起 HDAC2 阴性 RKO 细胞富集。5-氟尿嘧啶诱导 KAP1 的磷酸化，KAP1 是检查点激酶共济失调毛细血管扩张突变 (ATM) 的靶标，在 HDAC2 阴性细胞中比在 HDAC2 阳性对应细胞中更强。ATM 的药理学抑制使 RKO 细胞对 5-氟尿嘧啶的细胞毒性作用敏感。这些发现表明 HDAC2 和 ATM 调节结直肠癌细胞对 5-FU 的反应。
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