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BAP18 facilitates CTCF-mediated chromatin accessible to regulate enhancer activity in breast cancer

Cell Death & Differentiation volume 30, pages 1260–1278 (2023)Cite this article

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Abstract

The estrogen receptor alpha (ERα) signaling pathway is a crucial target for ERα-positive breast cancer therapeutic strategies. Co-regulators and other transcription factors cooperate for effective ERα-related enhancer activation. Recent studies demonstrate that the transcription factor CTCF is essential to participate in ERα/E2-induced enhancer transactivation. However, the mechanism of how CTCF is achieved remains unknown. Here, we provided evidence that BAP18 is required for CTCF recruitment on ERα-enriched enhancers, facilitating CTCF-mediated chromatin accessibility to promote enhancer RNAs transcription. Consistently, GRO-seq demonstrates that the enhancer activity is positively correlated with BAP18 enrichment. Furthermore, BAP18 interacts with SMARCA1/BPTF to accelerate the recruitment of CTCF to ERα-related enhancers. Interestingly, BAP18 is involved in chromatin accessibility within enhancer regions, thereby increasing enhancer transactivation and enhancer-promoter looping. BAP18 depletion increases the sensitivity of anti-estrogen and anti-enhancer treatment in MCF7 cells. Collectively, our study indicates that BAP18 coordinates with CTCF to enlarge the transactivation of ERα-related enhancers, providing a better understanding of BAP18/CTCF coupling chromatin remodeling and E-P looping in the regulation of enhancer transcription.

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Fig. 1: BAP18 recruits on global enhancer regions with CTCF.
Fig. 2: BAP18 facilitates a widespread increase in chromatin accessibility.
Fig. 3: E2/ERα-induced enhancer activation positively correlates with increased BAP18 recruitment.
Fig. 4: BAP18 interacts with NuRF complex and promotes CTCF recruitment on E2-related enhancers.
Fig. 5: BAP18 activates the transcriptional activity of TFF1 enhancers with CTCF.
Fig. 6: BAP18 facilitates enhancer-promoter looping of E2-related genes.
Fig. 7: BAP18 affects aromatase inhibitors and enhancer inhibitors in breast cancer cells.
Fig. 8: BAP18 is highly expressed in letrozole non-response patients.

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Data availability

The data and material that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Professor Kato Shigeaki from center of regional cooperation in Iwaki Meisei University for his important discussion and support. We appreciate Dr. Yunlong Huo and Dr. Fang Dong for their excellent technical assistance. We thank SeqHealth Tech Co., Ltd Wuhan, China, for ChIP-seq and ATAC-seq analysis.

Funding

This study was supported by the National Natural Science Foundation of China (32170603, 31871286 for YZ, 81872015, 82273123 for CW, 32100440 for GS); China Postdoctoral Science Foundation (276066) for GS; Foundation of Liaoning Province of China (LJKZ0756 for Shengli Wang); Local projects supported by the central government (2022JH6/100100035 for YZ); Foreign expert project of Ministry of Science and Technology (G2022006007L for YZ).

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Authors and Affiliations

  1. Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, Shenyang City, 110122, Liaoning Province, China

    Ge Sun, Baosheng Zhou, Manlin Wang, Ruina Luan, Yu Bai, Hao Li, Shan Wang, Dantong Zheng, Chunyu Wang, Shengli Wang, Kai Zeng, Shuchang Liu, Lin Lin, Mingcong He & Yue Zhao

  2. Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang City, 110042, Liaoning Province, China

    Yuntao Wei & Qiang Zhang

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Contributions

Conceptualization: GS and YZ. Methodology: GS. Software: YB, HL and MH. Validation: CW and YZ. Formal analysis: GS and YZ. Investigation: GS, BZ, MW, RL, DZ and SW. Resources: YW, SW, KZ, SL, and LL. Writing: GS and YZ. Supervision: QZ and YZ.

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Correspondence to Yue Zhao.

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Our study makes use of publicly available sequencing datasets as cited in the results section. As such, prior ethics approval has been obtained for these studies and no additional approval is required. All primary breast cancer tissues and adjacent tissues of patients were procured from the Liaoning Cancer Hospital of China Medical University, all of which received permission from patients already.

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Sun, G., Wei, Y., Zhou, B. et al. BAP18 facilitates CTCF-mediated chromatin accessible to regulate enhancer activity in breast cancer. Cell Death Differ 30, 1260–1278 (2023). https://doi.org/10.1038/s41418-023-01135-y

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