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 2

SAP30 promotes TNBC progression in mice.

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SAP30 promotes TNBC progression in mice. (A) Growth of SC and SAP30-KO1 ...
(A) Growth of SC and SAP30-KO1 or -KO2 MDA-MB-231 tumors in mice (n = 4). After harvesting, tumors were imaged (inset) and weighed (right). (B) In vivo bioluminescence imaging in mice after orthotopic implantation of SC or SAP30-KO1 MDA-MB-231 cells (n = 4–5). (C and D) Immunohistochemical staining (top) and quantification (bottom) of Ki67 (C), cleaved caspase-3 (CC3) (C), endomucin (D), and podoplanin (D) in SC and SAP30-KO1 or -KO2 MDA-MB-231 tumors (n = 4). (E) In vitro angiogenesis of HUVECs incubated with conditional media from SC or SAP30-KO1 or -KO2 MDA-MB-231 cells (top). Total tube length is quantified (bottom, n = 3). (F–I) Lung and liver metastasis in mice bearing SC or SAP30-KO1 or -KO2 MDA-MB-231 tumors by H&E staining (F, n = 4), qPCR (G and H, n = 4), and bioluminescence imaging assays (I, n = 4–5). (J) CTCs in blood from mice bearing SC or SAP30-KO1 or -KO2 MDA-MB-231 tumors by qPCR assay (n = 4). (K and L) Lung colonization of SC and SAP30-KO1 MDA-MB-231 cells by qPCR (K) and bioluminescence imaging (L) assays (n = 5). (M) Migration and invasion of SC and SAP30-KO1 or -KO2 MDA-MB-231 cells (left) and their quantification (right). n = 3. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Two-tailed Student’s t test (I and K); 1-way ANOVA with Dunnett’s test (A, right, C–E, G, H, J, and M); 2-way ANOVA with Dunnett’s test (A, left). Scale bars: 50 μm (C, D, and M), 100 μm (E and F).