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ACTR5 controls CDKN2A and tumor progression in an INO80-independent manner

Xiaobao Xu1, Anthony K N Chan1, Mingli Li1

  • 1Department of Systems Biology, Beckman Research Institute - City of Hope, Duarte, CA, USA.

Science Advances
|December 23, 2022
PubMed

Insights

Researchers identified ACTR5 (actin-related protein 5) as crucial for hepatocellular carcinoma (HCC) progression. Suppressing ACTR5 halts tumor growth by reactivating tumor suppressors, offering new therapeutic strategies for HCC.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Epigenetic alterations in cell cycle regulation are key drivers of hepatocellular carcinoma (HCC) tumorigenesis.
  • The precise epigenetic mechanisms governing aberrant cell cycle signaling and treatment responses in HCC are not fully understood.

Purpose of the Study:

  • To identify epigenetic regulators involved in HCC progression using a CRISPR interference screen.
  • To elucidate the role of ACTR5 and its associated complex in HCC cell cycle control and tumor growth.
  • To explore novel therapeutic strategies targeting ACTR5/IES6 in combination with cell cycle inhibitors.

Main Methods:

  • Conducted an epigenetics-focused CRISPR interference screen to identify key genes in HCC.
  • Utilized high-density CRISPR gene tiling to analyze ACTR5 and IES6 function in HCC.
  • Investigated the effects of ACTR5 suppression on cell cycle regulators (e.g., CDKN2A, CDK/E2F).
  • Assessed the synergistic effects of targeting ACTR5/IES6 and CDK inhibitors in HCC models.

Main Results:

  • ACTR5 (actin-related protein 5), a component of the INO80 complex, was identified as essential for HCC progression.
  • Suppression of ACTR5 led to CDKN2A activation, cell cycle arrest, and reduced HCC tumor growth.
  • ACTR5 and IES6 demonstrated an INO80-independent mechanism supporting HCC proliferation.
  • Combined targeting of ACTR5/IES6 and CDK inhibition showed synergistic therapeutic effects in HCC.

Conclusions:

  • ACTR5 plays a critical role in HCC tumorigenesis through modulation of cell cycle signaling.
  • The ACTR5/IES6 module represents a potential therapeutic target in HCC, possibly functioning independently of the canonical INO80 complex.
  • Combination therapy involving ACTR5/IES6 targeting and CDK inhibition offers a promising strategy for HCC treatment.

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