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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression
Lingli Jiang1, Rui Liang1, Qing Luo1
1College of Bioengineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University, Chongqing 400044, China.
Abstract:
Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays critical oncogenic roles in multiple cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in patients with HCC. Genetic depletion of Fto dramatically attenuated HCC progression in mice. Pharmacological inhibition of FTO by FB23/FB23-2 markedly suppressed the proliferation and migration of HCC cell lines in vitro and inhibited HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decrease in ERBB3 expression resulted in the inhibition of Akt-mTOR signaling, which subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 disturbed the stability of the tubulin cytoskeleton, whereas overexpression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrates that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells and highlights the potential of FTO inhibitors for targeting HCC.
Insights
Fat mass and obesity-associated protein (FTO) is a key driver in liver cancer. Inhibiting FTO with FB23-2 suppressed hepatocellular carcinoma (HCC) progression by targeting ERBB3 and TUBB4A, showing potential for new cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase implicated in various cancers.
- FTO's oncogenic roles suggest it as a potential therapeutic target in malignancies.
Purpose of the Study:
- To investigate the role of FTO in hepatocellular carcinoma (HCC) progression.
- To evaluate the efficacy of FTO inhibition as a therapeutic strategy for HCC.
Main Methods:
- Assessed FTO expression in HCC patients.
- Utilized genetic depletion and pharmacological inhibition (FB23/FB23-2) of FTO in HCC cell lines and mouse models.
- Investigated downstream molecular mechanisms involving m6A modification, ERBB3, TUBB4A, and Akt-mTOR signaling.
Main Results:
- FTO is highly expressed in HCC patients and its depletion attenuates HCC progression in mice.
- Pharmacological inhibition of FTO by FB23/FB23-2 suppressed HCC cell proliferation, migration, and tumorigenicity.
- FB23-2 increased m6A levels of ERBB3 and TUBB4A mRNA, leading to decreased ERBB3 expression and Akt-mTOR pathway inhibition.
- FB23-2 disrupted tubulin cytoskeleton stability, while TUBB4A overexpression rescued HCC cell migration.
Conclusions:
- FTO plays a critical oncogenic role in HCC by promoting cell proliferation and migration.
- FTO inhibition, particularly with FB23-2, represents a promising therapeutic strategy for hepatocellular carcinoma.
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