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Oncogenic zinc finger protein ZNF322A promotes stem cell-like properties in lung cancer through transcriptional suppression of c-Myc expression

Cell Death & Differentiation (2018) | Download Citation

Abstract

ZNF322A, a C2H2 zinc finger transcription factor, is an oncoprotein in lung cancer. However, the transcription mechanisms of ZNF322A in lung cancer stem cell-like reprogramming remain elusive. By integrating our chromatin immunoprecipitation-sequencing and RNA-sequencing datasets, we identified and validated the transcriptional targets of ZNF322A, which were significantly enriched in tumorigenic functions and developmental processes. Indeed, overexpression of ZNF322A promoted self-renewal ability and increased stemness-related gene expressions in vitro and in vivo. Importantly, ZNF322A bound directly to c-Myc promoter and recruited histone deacetylase 3 to transcriptionally suppress c-Myc expression, which in turn increased mitochondrial oxidative phosphorylation and promoted cell motility, thus maintaining stem cell-like properties of lung cancer. Clinically, ZNF322AHigh/c-MycLow expression profile was revealed as an independent indicator of poor prognosis in lung cancer patients. Our study provides the first evidence that ZNF322A-centered transcriptome promotes lung tumorigenesis and ZNF322A acts as a transcription suppressor of c-Myc to maintain lung cancer stem cell-like properties by shifting metabolism towards oxidative phosphorylation.

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Acknowledgements

This work was supported by Taiwan National Health Research Institutes [NHRI-EX107-10726BI], Taiwan Ministry of Science and Technology [MOST104-2627-B-006-001], and the Aim for the Top University Project Grant. We are grateful for the support from the Human Biobank, Research Center of Clinical Medicine, National Cheng Kung University Hospital for providing the clinical specimens and Ingenuity Pathway Analysis; and Taiwan Bioinformatics Core at the National Cheng Kung University, supported by a National Science Council for assisting with bioinformatics analyses.

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Affiliations

  1. Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan

    • Jayu Jen
    • , Chun-Yen Liu
    • , Yu-Ting Chen
    • , Li-Ting Wu
    • , Yang-Chih Shieh
    •  & Yi-Ching Wang
  2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan

    • Jayu Jen
    •  & Yi-Ching Wang
  3. Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY, 10016, USA

    • Jayu Jen
  4. Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan

    • Wu-Wei Lai

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The authors declare that they have no conflict of interest.

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Correspondence to Yi-Ching Wang.

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DOI

https://doi.org/10.1038/s41418-018-0204-6