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

Author

Listed:
  • Jieqiong Zhang

    (Technology and Research (A*STAR)
    National University of Singapore)

  • 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)
    University of Liverpool)

  • 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
    Technology and Research (A*STAR)
    National University of Singapore
    National University of Singapore)

  • Ravisankar Rajarethinam

    (Technology and Research (A*STAR))

  • Elina Pathak

    (Technology and Research (A*STAR))

  • Wai Leong Tam

    (National University of Singapore
    National University of Singapore
    Technology and Research (A*STAR)
    National University of Singapore)

  • Ern Yu Tan

    (Technology and Research (A*STAR)
    Tan Tock Seng Hospital
    Nanyang Technological University)

  • Wee-Wei Tee

    (Technology and Research (A*STAR)
    National University of Singapore
    National University of Singapore)

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.

Suggested Citation

  • 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 T, 2023. "Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38132-1
    DOI: 10.1038/s41467-023-38132-1
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