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

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 and Wee-Wei Tee ()
Additional contact information
Jieqiong Zhang: Technology and Research (A*STAR)
Zhenhua Hu: Technology and Research (A*STAR)
Hwa Hwa Chung: Technology and Research (A*STAR)
Yun Tian: Affiliated Hospital of Nanjing University of Chinese Medicine
Kah Weng Lau: National University Hospital
Zheng Ser: Technology and Research (A*STAR)
Yan Ting Lim: Technology and Research (A*STAR)
Radoslaw M. Sobota: Technology and Research (A*STAR)
Hwei Fen Leong: Technology and Research (A*STAR)
Benjamin Jieming Chen: Technology and Research (A*STAR)
Clarisse Jingyi Yeo: Technology and Research (A*STAR)
Shawn Ying Xuan Tan: Technology and Research (A*STAR)
Jian Kang: Technology and Research (A*STAR)
Dennis Eng Kiat Tan: Technology and Research (A*STAR)
Ieng Fong Sou: Technology and Research (A*STAR)
Urszula Lucja McClurg: University of Liverpool
Manikandan Lakshmanan: Technology and Research (A*STAR)
Thamil Selvan Vaiyapuri: Technology and Research (A*STAR)
Anandhkumar Raju: Technology and Research (A*STAR)
Esther Sook Miin Wong: Technology and Research (A*STAR)
Vinay Tergaonkar: National University Hospital
Ravisankar Rajarethinam: Technology and Research (A*STAR)
Elina Pathak: Technology and Research (A*STAR)
Wai Leong Tam: National University of Singapore
Ern Yu Tan: Technology and Research (A*STAR)
Wee-Wei Tee: Technology and Research (A*STAR)

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Cancer 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.

Date: 2023
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DOI: 10.1038/s41467-023-38132-1

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