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

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 8

SAP30 recruits the SIN3 complex to the chromatin and regulates chromatin accessibility in breast cancer cells.

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SAP30 recruits the SIN3 complex to the chromatin and regulates chromatin...
(A) Genomic distribution analysis of SAP30, SIN3A, and SIN3B in MDA-MB-231 cells (n = 2). (B) Venn diagram of overlapped ChIP-Seq peaks by SAP30, SIN3A, and SIN3B (n = 2). (C) Metagene plot and heatmap of ChIP-Seq assay showing occupancies of SAP30, SIN3A, and SIN3B on their coactivated genes (n = 2). RPKM, reads per kilobase per million mapped reads; TSS, transcription start site; TES, transcription end site. (D) ChIP-qPCR assay showing relative SIN3A and SIN3B occupancies on representative SAP30-, SIN3A/3B-coactivated genes in parental and SAP30-KO1 MDA-MB-231 cells (n = 3). (E) ChIP-qPCR assay showing relative SAP30 occupancy on representative SAP30-, SIN3A/3B-coactivated genes in parental and SIN3A/3B-DKO MDA-MB-231 cells (n = 3). (F) Metagene plot and heatmap of ATAC-seq assay showing chromatin accessibility on SAP30-, SIN3A/3B-coactivated genes in parental and SAP30-KO1 MDA-MB-231 cells (n = 3). (G) Metagene plot and heatmap of ChIP-Seq assay showing RNA polymerase II occupancy on SAP30-, SIN3A/3B-coactivated genes in parental and SAP30-KO1 MDA-MB-231 cells (n = 2). Data are mean ± SEM. **P < 0.01, ***P < 0.001, ****P < 0.0001. Two-way ANOVA with Tukey’s test (D and E).