Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis

Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis

Nature Communications

10.1038/s41467-023-38132-1

http://dx.doi.org/10.1038/s41467-023-38132-1

Jieqiong Zhang, Zhenhua Hu, Hwa Hwa Chung, Yun Tian, Kah Weng Lau, Zheng Ser, Yan Ting Lim, Radoslaw M. Sobota, Hwei Fen Leong, Benjamin Jieming Chen, Clarisse Jingyi Yeo, Shawn Ying Xuan Tan, Jian Kang, Dennis Eng Kiat Tan, Ieng Fong Sou, Urszula Lucja McClurg, Manikandan Lakshmanan, Thamil Selvan Vaiyapuri, Anandhkumar Raju, Esther Sook Miin Wong, Vinay Tergaonkar, Ravisankar Rajarethinam, Elina Pathak, Wai Leong Tam, Ern Yu Tan, Wee-Wei Tee

28 April 2023

Zhang, J., Hu, Z., Chung, H. H., Tian, Y., Lau, K. W., Ser, Z., Lim, Y. T., Sobota, R. M., Leong, H. F., Chen, B. J., Yeo, C. J., Tan, S. Y. X., Kang, J., Tan, D. E. K., Sou, I. F., McClurg, U. L., Lakshmanan, M., Vaiyapuri, T. S., Raju, A., … Tee, W.-W. (2023). Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-38132-1

AbstractCancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E leads to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identify the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate the expression of EMT markers, phenocopying NELF ablation. Elevated expression of NELF-E and KAT2B is associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Taken together, we uncover a crucial role of the NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the A*STAR - Career Development Fund
Grant Reference no. : 202D8046

This research / project is supported by the A*STAR - Career Development Fund
Grant Reference no. : 212D800074

This research / project is supported by the National Research Foundation - Competitive Research Programme
Grant Reference no. : NRF-CRP26-2021- 0001

This research / project is supported by the National Medical Research Council - Open Fund - Individual Research Grant
Grant Reference no. : NMRC-OFIRG21jun-0101

This research / project is supported by the National Research Foundation - NRF Fellowship program
Grant Reference no. : NRF-NRFF2016-06

This research / project is supported by the National Medical Research Council - Open Fund - Individual Research Grant
Grant Reference no. : NMRC-OFIRG21nov-0027

This research is supported by core funding from: A*STAR
Grant Reference no. :

This research / project is supported by the National Research Foundation - NRF-SIS “SingMass”
Grant Reference no. : N.A

Target Translation Consortium (TTC2020_002), Singapore Therapeutic Development Review (STDR) Pilot (H22H9a0075) and the UIBR award.

https://oar.a-star.edu.sg/communities-collections/articles/16332

2041-1723

Institute of Molecular and Cell Biology