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SAP30 promotes breast tumor progression by bridging the transcriptional corepressor SIN3 complex and MLL1
- Source :
- Journal of Clinical Investigation. September, 2023, Vol. 133 Issue 17
- Publication Year :
- 2023
-
Abstract
- SAP30 is a core subunit of the transcriptional corepressor SIN3 complex, but little is known about its role in gene regulation and human cancer. Here, we show that SAP30 was a nonmutational oncoprotein upregulated in more than 50% of human breast tumors and correlated with unfavorable outcomes in patients with breast cancer. In various breast cancer mouse models, we found that SAP30 promoted tumor growth and metastasis through its interaction with SIN3A/3B. Surprisingly, the canonical gene silencing role was not essential for SAP30's tumor-promoting actions. SAP30 enhanced chromatin accessibility and RNA polymerase II occupancy at promoters in breast cancer cells, acting as a coactivator for genes involved in cell motility, angiogenesis, and lymphangiogenesis, thereby driving tumor progression. Notably, SAP30 formed a homodimer with 1 subunit binding to SIN3A and another subunit recruiting MLL1 through specific Phe186/200 residues within its transactivation domain. MLL1 was required for SAP30-mediated transcriptional coactivation and breast tumor progression. Collectively, our findings reveal that SAP30 represents a transcriptional dependency in breast cancer.<br />Introduction Breast cancer is the most common malignant disease in women, with many patients dying of metastasis. The development of breast cancer toward distant metastasis is a harsh process, wherein [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 133
- Issue :
- 17
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.763929741
- Full Text :
- https://doi.org/10.1172/JCI168362