Novillo Apolonia, Fernández-Santander Ana, Gaibar Maria, Galán Miguel, Romero-Lorca Alicia, El Abdellaoui-Soussi Fadoua, Gómez-Del Arco Pablo
Department of Pre-clinical Dentistry, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain.
Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain.
Front Oncol. 2021 Apr 26;11:633233. doi: 10.3389/fonc.2021.633233. eCollection 2021.
Chromodomain-helicase-DNA-binding protein 4 (CHD4) is an epigenetic regulator identified as an oncogenic element that may provide a novel therapeutic target for the treatment of breast cancer (BC). CHD4-the core component of the nucleosome remodeling and deacetylase (NuRD) complex-may be mutated in patients with this disease. However, information on mutants that might allow their use as biomarkers of therapeutic success and prognosis is lacking. The present work examines mutations in reported in patients with breast cancer and included in public databases and attempts to identify their roles in its development. The databases revealed 81 point mutations across different types of breast cancer (19 of which also appeared in endometrial, intestinal, nervous system, kidney, and lymphoid organ cancers). 71.6% of the detected mutations were missense mutations, 13.6% were silent, and 6.2% nonsense. Over 50% affected conserved residues of the ATPase motor (ATPase and helicase domains), and domains of unknown function in the C-terminal region. Thirty one mutations were classified in the databases as either 'deleterious', 'probably/possibly damaging' or as 'high/medium pathogenic'; another five nonsense and one splice-site variant were predicted to produce potentially harmful truncated proteins. Eight of the 81 mutations were categorized as putative driver mutations and have been found in other cancer types. Some mutations seem to influence ATPase and DNA translocation activities (R1162W), while others may alter protein stability (R877Q/H, R975H) or disrupt DNA binding and protein activity (R572*, X34_splice) suggesting CHD4 function may be affected. tumorigenecity studies in endometrial cancer have revealed R975H and R1162W as mutations that lead to CHD4 loss-of-function. Our study provides insight into the molecular mechanism whereby CHD4, and some of its mutants could play a role in breast cancer and suggest important implications for the biological comprehension and prognosis of breast cancer, identifying as a novel therapeutic target for BC patients.
染色质结构域解旋酶DNA结合蛋白4（CHD4）是一种表观遗传调节因子，被确定为一种致癌因素，可能为乳腺癌（BC）的治疗提供新的治疗靶点。CHD4是核小体重塑和去乙酰化酶（NuRD）复合物的核心成分，在该病患者中可能发生突变。然而，缺乏关于可能用作治疗成功和预后生物标志物的突变体的信息。本研究调查了乳腺癌患者报告的、包含在公共数据库中的CHD4突变，并试图确定它们在乳腺癌发生发展中的作用。数据库显示，不同类型乳腺癌中存在81个点突变（其中19个也出现在子宫内膜癌、肠癌、神经系统癌、肾癌和淋巴器官癌中）。检测到的突变中，71.6%为错义突变，13.6%为沉默突变，6.2%为无义突变。超过50%的突变影响ATP酶马达的保守残基（ATP酶和螺旋酶结构域）以及C端区域功能未知的结构域。31个突变在数据库中被分类为“有害”、“可能/可能有害”或“高/中致病性”；另外5个无义突变和1个剪接位点变异预计会产生潜在有害的截短蛋白。81个突变中的8个被归类为假定的驱动突变，并且在其他癌症类型中也有发现。一些突变似乎影响ATP酶和DNA易位活性（R1162W），而其他突变可能改变蛋白质稳定性（R877Q/H、R975H）或破坏DNA结合和蛋白质活性（R572*、X34_splice），这表明CHD4的功能可能受到影响。子宫内膜癌的肿瘤发生研究表明，R975H和R1162W是导致CHD4功能丧失的突变。我们的研究深入了解了CHD4及其一些突变体可能在乳腺癌中发挥作用的分子机制，并对乳腺癌的生物学理解和预后提出了重要意义，确定CHD4为BC患者的一个新的治疗靶点。
