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Updated: Feb 10, 2026
Author Spotlight: Investigating Liver Cancer Pathogenesis Using Patient-Derived Organoids
Published on: August 18, 2023
MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA
Zhongwei Cao1, Hua Fan-Minogue, David I Bellovin
1Division of Medical Oncology, Department of Medicine and Pathology, Molecular Imaging Program at Stanford, Stanford University, Stanford, California 94305, USA.
Abstract:
MYC is a potential target for many cancers but is not amenable to existing pharmacologic approaches. Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) by statins has shown potential efficacy against a number of cancers. Here, we show that inhibition of HMG-CoA reductase by atorvastatin (AT) blocks both MYC phosphorylation and activation, suppressing tumor initiation and growth in vivo in a transgenic model of MYC-induced hepatocellular carcinoma (HCC) as well as in human HCC-derived cell lines. To confirm specificity, we show that the antitumor effects of AT are blocked by cotreatment with the HMG-CoA reductase product mevalonate. Moreover, by using a novel molecular imaging sensor, we confirm that inhibition of HMG-CoA reductase blocks MYC phosphorylation in vivo. Importantly, the introduction of phosphorylation mutants of MYC at Ser62 or Thr58 into tumors blocks their sensitivity to inhibition of HMG-CoA reductase. Finally, we show that inhibition of HMG-CoA reductase suppresses MYC phosphorylation through Rac GTPase. Therefore, HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation, and tumorigenic properties. The inhibition of HMG-CoA reductase may be a useful target for the treatment of MYC-associated HCC as well as other tumors.
Insights
Statins like atorvastatin inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), blocking MYC activation and suppressing hepatocellular carcinoma (HCC) growth. This offers a new therapeutic strategy for MYC-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- MYC is a crucial oncogene implicated in numerous cancers.
- Current pharmacologic strategies targeting MYC are limited.
- Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), show promise in cancer therapy.
Purpose of the Study:
- To investigate the efficacy of HMG-CoA reductase inhibition by atorvastatin (AT) against MYC-driven hepatocellular carcinoma (HCC).
- To elucidate the molecular mechanisms by which AT affects MYC phosphorylation and activation.
- To evaluate AT as a potential therapeutic agent for MYC-associated malignancies.
Main Methods:
- Utilized a transgenic model of MYC-induced HCC and human HCC cell lines.
- Administered atorvastatin (AT) and assessed tumor initiation and growth.
- Confirmed specificity using mevalonate, a product of HMG-CoA reductase.
- Employed a novel molecular imaging sensor to monitor MYC phosphorylation in vivo.
- Introduced MYC phosphorylation mutants (Ser62, Thr58) to assess drug sensitivity.
- Investigated the role of Rac GTPase in the AT-mediated suppression of MYC phosphorylation.
Main Results:
- AT effectively inhibited MYC phosphorylation and activation, suppressing tumor initiation and growth in both preclinical models and cell lines.
- The antitumor effects of AT were reversed by mevalonate, confirming target specificity.
- Inhibition of HMG-CoA reductase was shown to block MYC phosphorylation in vivo.
- Tumors expressing MYC phosphorylation mutants (Ser62 or Thr58) were resistant to AT treatment.
- AT-induced suppression of MYC phosphorylation was mediated through Rac GTPase.
Conclusions:
- HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation, and tumorigenic potential.
- Inhibition of HMG-CoA reductase by atorvastatin represents a promising therapeutic strategy for MYC-driven HCC and potentially other cancers.
- Targeting HMG-CoA reductase offers a novel approach for treating cancers dependent on MYC signaling.
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