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Assays for Validating Histone Acetyltransferase Inhibitors
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HDAC2 links ubiquitination to tumor suppression in synovial sarcoma

Christina Cooley1, Le Su1

  • 1HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.

Molecular & Cellular Oncology
|May 24, 2021
PubMed

Insights

Histone deacetylase 2 (HDAC2) controls cancer protein stability through a novel pathway involving MDM2. Inactivating HDAC2 effectively degrades SS18-SSX oncoproteins, offering a therapeutic strategy for synovial sarcoma.

Area of Science:

  • Molecular biology
  • Cancer research
  • Epigenetics

Background:

  • Histone deacetylase 2 (HDAC2) is known for its role in gene transcription and cancer development.
  • Its involvement in oncogenesis is well-documented, but non-transcriptional functions are less understood.

Purpose of the Study:

  • To investigate a transcription-independent pathway regulated by HDAC2.
  • To explore HDAC2's role in controlling the stability of cancer-related proteins.
  • To assess the therapeutic potential of targeting HDAC2 in synovial sarcoma.

Main Methods:

  • Investigated the interaction between HDAC2 and MDM2 (mouse double minute 2 homolog) ubiquitin ligase.
  • Analyzed the effect of HDAC2 inactivation on SS18-SSX oncoprotein stability.
  • Evaluated the therapeutic efficacy of HDAC2 inhibition in a synovial sarcoma model.

Main Results:

  • Identified a novel, transcription-independent pathway where HDAC2 influences protein stability via MDM2.
  • Demonstrated that HDAC2 inactivation leads to the degradation of the SS18-SSX oncoprotein.
  • Showcased significant therapeutic effects of HDAC2 inactivation in synovial sarcoma.

Conclusions:

  • HDAC2 possesses a critical, non-transcriptional function in regulating cancer-related protein stability through the MDM2 ubiquitin ligase.
  • Targeting HDAC2 offers a promising therapeutic avenue for synovial sarcoma by degrading the SS18-SSX driver oncoprotein.
Keywords:
HDAC2MDM2MULEacetylationsynovial sarcomatargeted therapeuticsubiquitination

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