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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 2439 (04 28 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 37117180 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Chromatin
• KAT2B protein, human
• negative elongation factor
• p300-CBP Transcription Factors
• Snail Family Transcription Factors
• Transcription Factors
• SNAI1 protein, human

Topics

• Female
• Humans
• Breast Neoplasms (pathology)
• Carcinogenesis (genetics)
• Cell Line, Tumor
• Chromatin
• Epigenesis, Genetic
• Epithelial-Mesenchymal Transition (genetics)
• Gene Expression Regulation, Neoplastic
• p300-CBP Transcription Factors (metabolism)
• Snail Family Transcription Factors (metabolism)
• Transcription Factors (metabolism)