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TiPARP forms nuclear condensates to degrade HIF-1α and suppress tumorigenesis

Lu Zhang1, Ji Cao1, Longying Dong2

  • 1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853.

Proceedings of the National Academy of Sciences of the United States of America
|June 3, 2020
PubMed

Insights

This study reveals TiPARP as a key deactivator for oncogenic transcription factors like HIF-1. Activating TiPARP demonstrates significant antitumor effects, suggesting a novel anticancer strategy.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Research

Background:

  • Transcription factor activity requires precise control, including deactivation.
  • Oncogenic transcription factors like HIF-1 play roles in cancer development.
  • Mechanisms for deactivating transcription factors are not fully understood.

Purpose of the Study:

  • To elucidate the deactivation mechanism of HIF-1 and other oncogenic transcription factors.
  • To investigate the role of TiPARP in transcription factor regulation.
  • To explore the potential of TiPARP as an anticancer therapeutic target.

Main Methods:

  • Investigated the interaction between HIF-1 and TiPARP.
  • Utilized cell culture and mouse xenograft models to assess TiPARP's function.
  • Examined the role of ADP ribosylation in TiPARP-mediated deactivation.

Main Results:

  • HIF-1 promotes the transcription of TiPARP, an ADP ribosyltransferase.
  • TiPARP forms nuclear bodies that recruit HIF-1α and the E3 ubiquitin ligase HUWE1.
  • TiPARP-mediated degradation of HIF-1α, c-Myc, and estrogen receptor was observed.
  • TiPARP demonstrated significant antitumor effects in vitro and in vivo.

Conclusions:

  • TiPARP acts as a negative-feedback regulator for multiple oncogenic transcription factors.
  • Protein ADP-ribosylation plays a role in transcription factor deactivation.
  • Activating TiPARP presents a promising anticancer strategy.
Keywords:
ADP-ribosylationHIF-1TiPARPnuclear condensatesubiquitination

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