Background/Objectives: SCCOHT is an aggressive and often fatal cancer that belongs to the ~20% of cancers defined by mutations to subunits of the SWI/SNF chromatin remodeling complex. In SCCOHT, mutations to theSMARCA4gene, which encodes the SWI/SNF ATPase BRG1, are sufficient to impair SWI/SNF function. This single genetic lesion leads to a cascade of events that promote tumorigenesis, some of which may involve the intersection of SWI/SNF with oncogenic pathways such as those regulated by theMYConcogene. In SCCOHT tumors and other cancers marked by SWI/SNF subunit mutation, MYC target genes are recurrently activated, pointing to a relationship between SWI/SNF and MYC that has yet to be fully explored. Methods: In this study, we investigate the contribution of MYC to SCCOHT biology by performing a combination of chromatin binding and transcriptome assays in genetically engineered SCCOHT cell lines, with subsequent validation using patient tumor expression data. Results: We find that MYC binds to thousands of active promoters in the BIN-67 SCCOHT cell line and that the depletion of MYC results in a broad range of gene expression changes with a notable effect on the expression of genes related to DNA repair. We uncover an MYC-regulated DNA repair gene expression program in BIN-67 cells that is antagonized by BRG1 reintroduction. Finally, we identify a DNA repair gene signature that is upregulated in SCCOHT tumors and in tumors defined by loss of the SWI/SNF subunit SNF5. Conclusions: Collectively, these data implicate MYC as a robust regulator of DNA repair gene expression in SCCOHT and lay a foundation for future studies focused on interrogating the relationship between BRG1 and MYC.
背景/目的：小细胞卵巢高钙血症型肿瘤（SCCOHT）是一种侵袭性强且常致命的癌症，属于约20%由SWI/SNF染色质重塑复合体亚基突变定义的癌症类型。在SCCOHT中，编码SWI/SNF ATP酶BRG1的SMARCA4基因突变足以损害SWI/SNF功能。这一单一遗传损伤引发一系列促进肿瘤发生的事件，其中部分可能涉及SWI/SNF与致癌通路（如MYC原癌基因调控通路）的交叉作用。在SCCOHT肿瘤及其他以SWI/SNF亚基突变为特征的癌症中，MYC靶基因被反复激活，提示SWI/SNF与MYC之间存在尚未被充分探索的关联。方法：本研究通过基因工程改造的SCCOHT细胞系，结合染色质结合与转录组分析，并利用患者肿瘤表达数据进行验证，探究MYC在SCCOHT生物学中的作用。结果：我们发现MYC在BIN-67 SCCOHT细胞系中结合数千个活性启动子，敲低MYC可引起广泛的基因表达变化，尤其对DNA修复相关基因的表达产生显著影响。我们在BIN-67细胞中发现了一个受MYC调控的DNA修复基因表达程序，该程序可被重新引入的BRG1拮抗。最后，我们鉴定出一个在SCCOHT肿瘤及SNF5亚基缺失的肿瘤中上调的DNA修复基因特征集。结论：这些数据共同表明MYC是SCCOHT中DNA修复基因表达的关键调控因子，为未来深入研究BRG1与MYC之间的相互作用关系奠定了基础。
肿瘤(癌症)患者之家