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

• Main Authors: Zhang, Jieqiong, Hu, Zhenhua, Chung, Hwa Hwa, Tian, Yun, Lau, Kah Weng, Ser, Zheng, Lim, Yan Ting, Sobota, Radoslaw M., Leong, Hwei Fen, Chen, Benjamin Jieming, Yeo, Clarisse Jingyi, Tan, Shawn Ying Xuan, Kang, Jian, Tan, Dennis Eng Kiat, Sou, Ieng Fong, McClurg, Urszula Lucja, Lakshmanan, Manikandan, Vaiyapuri, Thamil Selvan, Raju, Anandhkumar, Wong, Esther Sook Miin, Tergaonkar, Vinay, Rajarethinam, Ravisankar, Pathak, Elina, Tam, Wai Leong, Tan, Ern Yu, Tee, Wee-Wei
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Medicine; Elongation Factor; Cancer Prognosis
• Online Access: https://hdl.handle.net/10356/169765
• Institution: Nanyang Technological University

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.