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SAP30 promotes breast tumor progression by bridging the transcriptional corepressor SIN3 complex and MLL1
Lei Bao, … , Yingfei Wang, Weibo Luo
Lei Bao, … , Yingfei Wang, Weibo Luo
Published September 1, 2023
Citation Information: J Clin Invest. 2023;133(17):e168362. https://doi.org/10.1172/JCI168362.
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Research Article Oncology

SAP30 promotes breast tumor progression by bridging the transcriptional corepressor SIN3 complex and MLL1

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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.

Authors

Lei Bao, Ashwani Kumar, Ming Zhu, Yan Peng, Chao Xing, Jennifer E. Wang, Yingfei Wang, Weibo Luo

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Figure 1

SAP30 is upregulated in human breast tumors.

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SAP30 is upregulated in human breast tumors.
(A–C) Representative SAP30 ...
(A–C) Representative SAP30 immunohistochemical staining in human ER+ and HER2+ breast tumors and adjacent normal tissues (A). Staining is quantified with H-score (B and C). (D and E) Representative SAP30 immunohistochemical staining in a human TNBC TMA (D). Staining is quantified with intensity score (0–3, E). ND, not detected. (F and G) Representative SAP30 immunohistochemical staining in human paired primary and metastatic breast tumors (F). Staining is quantified with H-score (G). *P < 0.05, **P < 0.01. Paired 2-tailed Student’s t test (B, C, and G); χ2 test (E). Scale bars: 50 μm (A and F), 200 μm (D).

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