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ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma

Beibei Liang1, Rui Chen2, Shaohua Song3

  • 1Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, 201318, Shanghai, China.

Cell Death & Disease
|November 6, 2019
PubMed

Insights

The tumor suppressor ASPP2 inhibits hepatocellular carcinoma (HCC) growth by regulating the mevalonate pathway. Inhibiting this pathway with simvastatin reduces tumor progression, offering a potential new therapy for HCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hepatocellular carcinoma (HCC) growth depends on cellular energy and nutrient supply.
  • The tumor suppressor ASPP2, an activator of p53, plays a role in cell growth regulation.
  • The mevalonate pathway is crucial for cellular biosynthesis and energy production.

Purpose of the Study:

  • To investigate the role of ASPP2 in regulating the mevalonate pathway in HCC.
  • To determine the impact of ASPP2 on HCC cell proliferation, chemoresistance, and tumor growth.
  • To explore the therapeutic potential of targeting the mevalonate pathway in HCC.

Main Methods:

  • Gene expression profiling to analyze mevalonate pathway enzyme expression in response to ASPP2 levels.
  • In vitro assays to assess HCC cell proliferation, anchorage-independent growth, and chemoresistance.
  • In vivo studies using xenografted nude mice to evaluate tumor growth inhibition.
  • Mechanistic studies involving protein-protein interaction assays (ASPP2-SREBP-2) and transcriptional activity analysis.
  • Analysis of clinical data correlating ASPP2 and HMGCR levels with patient prognosis.

Main Results:

  • Downregulation of ASPP2 in HCC leads to increased expression of mevalonate pathway enzymes, elevated cholesterol levels, and enhanced tumor-initiating capacity.
  • Simvastatin, a mevalonate pathway inhibitor, effectively suppressed ASPP2 depletion-induced phenotypes, including anchorage-independent proliferation, chemoresistance, and tumor growth in vivo.
  • ASPP2 interacts with SREBP-2 in the nucleus, inhibiting its transcriptional activity on target genes, including key mevalonate pathway enzymes.
  • Clinical data indicate that high ASPP2 levels and low HMGCR levels correlate with better patient prognosis.

Conclusions:

  • ASPP2 negatively regulates the mevalonate pathway in HCC by inhibiting SREBP-2 transcriptional activity.
  • The mevalonate pathway is critical for HCC initiation and progression, and its inhibition represents a promising therapeutic strategy.
  • Targeting the ASPP2-mevalonate pathway axis offers a novel therapeutic opportunity for hepatocellular carcinoma.

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