Edwards Andrea D, Dai Yangyang, Singh Siddharth, Thornton Micah, Nandu Tulip, Kittler Ralf, Camacho Cristel V, Huang Dan, Kraus W Lee
Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, United States.
Current address: Arkansas Children's Research Institute, Little Rock, AR 72202, USA.
bioRxiv. 2025 May 3:2025.04.29.651098. doi: 10.1101/2025.04.29.651098.
Although mutations in genes encoding histones display a similar prevalence to that of some other somatic mutations in cancer, the underlying mechanisms by which histone mutations drive tumorigenesis have not been fully explored. Herein, we curated missense mutations occurring in core histone genes in breast cancers using data from MSK-IMPACT and cBioPortal to identify high frequency breast cancer-associated histone gene mutations. We characterized 17 high frequency oncohistone mutations in H2A H2B, and H3 that are enriched in breast cancer samples and occurred at glutamate (E), aspartate (D), serine (S), and arginine (R) residues. Many of these mutants co-occur with mutations in breast cancer samples. The oncohistone mutants were expressed in MCF-7 breast cancer cells or MCF-10A mammary epithelial cells and screened for effects on oncogenic phenotypes in a variety of cell- and tumor-based assays (i.e., proliferation, migration, invasion, competitive outgrowth, transformation). In addition, we examined the effects of selected mutants on DNA damage and gene expression. Our results indicate that the collection of oncohistone mutants that we screened have varying phenotypic and functional effects. Some can promote cancer-related phenotypes, with H2B-E76Q, H3-E97K, and H3-E105K eliciting strong oncogenic phenotypes and alterations in gene expression. All three of these mutants showed cooperativity with an activating mutation in PIK3CA (E545K), or a chemical activator of PI3Kα (UCL-TRO-1938), in assays of MCF-10A proliferation. H3-E105K also strongly promoted transformation of MCF-10A cells in an assay of growth on low attachment substrate independently of PIK3CA. Our results indicate that some high frequency oncohistone mutants can have oncogenic activity in breast cancers, and may act as potential cancer drivers. Collectively, these observations presented here can be used as a resource to connect biological and molecular outcomes to oncohistones in breast cancers.
尽管编码组蛋白的基因突变与癌症中其他一些体细胞突变的发生率相似，但组蛋白突变驱动肿瘤发生的潜在机制尚未得到充分探索。在此，我们利用MSK-IMPACT和cBioPortal的数据，整理了乳腺癌核心组蛋白基因中发生的错义突变，以识别与乳腺癌相关的高频组蛋白基因突变。我们对H2A、H2B和H3中17个高频致癌组蛋白突变进行了表征，这些突变在乳腺癌样本中富集，且发生在谷氨酸（E）、天冬氨酸（D）、丝氨酸（S）和精氨酸（R）残基处。其中许多突变体在乳腺癌样本中与其他突变共同出现。这些致癌组蛋白突变体在MCF-7乳腺癌细胞或MCF-10A乳腺上皮细胞中表达，并在各种基于细胞和肿瘤的实验（即增殖、迁移、侵袭、竞争性生长、转化）中筛选其对致癌表型的影响。此外，我们研究了选定突变体对DNA损伤和基因表达的影响。我们的结果表明，我们筛选的致癌组蛋白突变体集合具有不同的表型和功能效应。一些可以促进癌症相关表型，H2B-E76Q、H3-E97K和H3-E105K引发强烈的致癌表型和基因表达改变。在MCF-10A增殖实验中，这三个突变体均显示出与PIK3CA激活突变（E545K）或PI3Kα化学激活剂（UCL-TRO-1938）的协同作用。在低附着底物上生长的实验中，H3-E105K还强烈促进了MCF-10A细胞的转化，且不依赖于PIK3CA。我们的结果表明，一些高频致癌组蛋白突变体在乳腺癌中可能具有致癌活性，并可能作为潜在的癌症驱动因素。总体而言，这里呈现的这些观察结果可作为一种资源，将生物学和分子结果与乳腺癌中的致癌组蛋白联系起来。
