The roles of
chromatin remodelers and their underlying mechanisms of action in
cancer remain unclear. In this study, SMARCB1, known initially as a bona fide tumor suppressor gene, was investigated in
liver cancer. SMARCB1 was highly upregulated in patients with
liver cancer and was associated with poor prognosis. Loss- and gain-of-function studies in liver cells revealed that SMARCB1 loss led to reduced cell proliferation, wound healing capacity, and
tumor growth in vivo. Although upregulated SMARCB1 appeared to contribute to switch/
sucrose nonfermentable (SWI/SNF) complex stability and integrity, it did not act using its known pathways antagonism with EZH2 or association between TP53 or AMPK. SMARCB1 knockdown induced a mild reduction in global H3K27 acetylation, and
chromatin immunoprecipitation sequencing of SMARCB1 and acetylated
histone H3K27
antibodies before and after SMARCB1 loss identified Nucleoporin210 (NUP210) as a critical target of SMARCB1, which bound its enhancer and changed H3K27Ac enrichment and downstream gene expression, particularly
cholesterol homeostasis and
xenobiotic metabolism. Notably, NUP210 was not only a putative
tumor supporter involved in
liver cancer but also acted as a key scaffold for SMARCB1 and P300 to
chromatin. Furthermore, SMARCB1 deficiency conferred sensitivity to
doxorubicin and P300 inhibitor in
liver cancer cells. These findings provide insights into mechanisms underlying dysregulation of
chromatin remodelers and show novel associations between
nucleoporins and
chromatin remodelers in
cancer. SIGNIFICANCE: This study reveals a novel protumorigenic role for SMARCB1 and describes valuable links between
nucleoporins and
chromatin remodelers in
cancer by identifying NUP210 as a critical coregulator of SMARCB1 chromatin remodeling activity.