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CHD1 is a synthetic lethal vulnerability in MYC-driven breast cancer [RNA-Seq]

ABSTRACT: c-MYC (MYC) is a transcription factor that regulates gene expression during growth stages under developmental and physiological conditions, and its dysregulation often results in cancer. Understanding how over-activation of MYC leads to transformation and tumour growth may provide new therapeutic avenues in a variety of cancers. The function of Chromodomain-Helicase DNA-binding 1 (CHD1), a chromatin remodeler that plays essential roles in stem/progenitor cells during development, has not been explored in MYC-driven cancer. By intersecting two independent genome-wide screens, we identified loss of CHD1 as a potential synthetic lethal relationship with MYC activation in breast cancer. Using a xenograft model of MYC-driven breast cancer, we found that knockdown of CHD1 suppresses tumour growth. This finding is further supported in vitro, where knockdown of CHD1 in breast epithelial cells results in significant decreases in cell proliferation and transformation, and in increased cell death. Importantly, this CHD1 dependency is observed only when MYC is over-expressed. Knockdown of CHD1 leads to a prominent reduction in chromatin accessibility, in particular at genomic regions associated with tumour progression and invasion. Transcriptional analyses and follow-up experiments reveal that knockdown of CHD1 induces defects in nucleolar architecture and activation of p53. Taken together, these findings shed light on the chromatin-level regulation of MYC-driven breast cancer and uncover CHD1 as a novel therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303747 | GEO | 2026/02/26

REPOSITORIES: GEO

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CHD1 is a synthetic lethal vulnerability in MYC-driven breast cancer [ATAC-seq]

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