Targeting the mevalonate pathway is a novel therapeutic approach to inhibit oncogenic FoxM1 transcription factor in human hepatocellular carcinoma

// Satoshi Ogura 1, * , Yuichi Yoshida 1, * , Tomohide Kurahashi 1 , Mayumi Egawa 1 , Kunimaro Furuta 1 , Shinichi Kiso 1 , Yoshihiro Kamada 1, 2 , Hayato Hikita 1 , Hidetoshi Eguchi 3 , Hisakazu Ogita 4 , Yuichiro Doki 3 , Masaki Mori 3 , Tomohide Tatsumi 1 and Tetsuo Takehara 1 1 Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan 2 Department of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan 3 Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan 4 Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan * These authors are contributed equally to this work Correspondence to: Tetsuo Takehara, email: takehara@gh.med.osaka-u.ac.jp Yuichi Yoshida, email: yyoshida@gh.med.osaka-u.ac.jp Keywords: cancer metabolism; FOXM1; hepatocellular carcinoma; mevalonate pathway; statin Received: October 31, 2017      Accepted: February 24, 2018      Published: April 20, 2018 ABSTRACT Dysregulation of cell metabolism is a hallmark of cancer. The mevalonate pathway in lipid metabolism has been implicated as a potential target of cancer therapy for hepatocellular carcinoma (HCC). The role of the Forkhead Box M1 (FoxM1) transcription factor in HCC development has been well documented, however, its involvement in cancer metabolism of HCC has not been fully determined. Here, we hypothesized that FoxM1 is involved in the mevalonate pathway of cholesterol biosynthesis in HCC. Inhibition of the mevalonate pathway by statins, inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), resulted in reduced expression of FoxM1 and increased cell death in human hepatoma cells. Re-exposure of mevalonate, a product of HMGCR, restored these effects. Likewise, knockdown of HMGCR reduced FoxM1 expression, indicating that FoxM1 expression was regulated by the mevalonate pathway in HCC. Mechanistically, protein geranylgeranylation was found to be responsible for FoxM1 expression and geranylgeranylated proteins, including RhoA, Rac1 or Cdc42, were shown to be involved in this process. In surgically resected human HCC tissues, the gene expression of FoxM1 had a positive correlation with that of the mevalonate pathway-related genes, such as HMGCR or sterol regulatory element-binding protein 2 ( SREBP2 ). Furthermore, the gene expression of FoxM1 along with that of HMGCR or SREBP2 defined prognosis of HCC patients, suggesting the clinical significance of the mevalonate-FoxM1 pathway in human HCC. Our data indicate that FoxM1 links the mevalonate pathway to oncogenic signals in HCC. Thus, we propose a novel therapeutic approach to inhibit FoxM1 by targeting the mevalonate pathway for HCC.