Abstract
SMARCB1 encodes the SNF5 subunit of the SWI/SNF chromatin remodeler. SNF5 also interacts with the oncoprotein transcription factor MYC and is proposed to stimulate MYC activity. The concept that SNF5 is a coactivator for MYC, however, is at odds with its role as a tumor-suppressor, and with observations that loss of SNF5 leads to activation of MYC target genes. Here, we reexamine the relationship between MYC and SNF5 using biochemical and genome-wide approaches. We show that SNF5 inhibits the DNA-binding ability of MYC and impedes target gene recognition by MYC in cells. We further show that MYC regulation by SNF5 is separable from its role in chromatin remodeling, and that reintroduction of SNF5 into SMARCB1-null cells mimics the primary transcriptional effects of MYC inhibition. These observations reveal that SNF5 antagonizes MYC and provide a mechanism to explain how loss of SNF5 can drive malignancy.
Highlights
SMARCB1 encodes the SNF5 subunit of the SWI/SNF chromatin remodeler
The concept that SNF5 is a coactivator for MYC, conflicts with its well-established role as a tumor suppressor, with a report that SNF5 and MYC oppositely regulate a common set of genes[21], with findings that loss of SNF5 in cancer is associated with activation of MYC target gene signatures[8,9,10], and with recent observations that MYC inhibition can restrict rhabdoid tumor growth in vivo[23]
SNF5 binds within the basic helix-loop-helix leucine zipper (bHLHZip), and it has little if any effect on the MYC–MAX interaction[21], the impact of SNF5 on the DNAbinding ability of full-length MYC:MAX heterodimers has not been determined
Summary
SMARCB1 encodes the SNF5 subunit of the SWI/SNF chromatin remodeler. SNF5 interacts with the oncoprotein transcription factor MYC and is proposed to stimulate MYC activity. The concept that SNF5 is a coactivator for MYC, conflicts with its well-established role as a tumor suppressor, with a report that SNF5 and MYC oppositely regulate a common set of genes[21], with findings that loss of SNF5 in cancer is associated with activation of MYC target gene signatures[8,9,10], and with recent observations that MYC inhibition can restrict rhabdoid tumor growth in vivo[23] Given these disparities, it is clear that both the functional significance of the SNF5–MYC interaction—and the underlying mechanisms involved—are unresolved. These observations show that SNF5 tempers target gene recognition by MYC, providing a mechanism to account for enhanced MYC function in MRT and suggesting that the tumor-suppressive functions of SNF5 are mediated, at least in part, by inhibiting MYC
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