Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression [MeRIP]

Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays a critical oncogenic role in various cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in clinical patients of HCC and presents as a poor prognostic factor. Genetic depletion of FTO dramatically attenuated HCC progression in vivo. Pharmacological inhibition of FTO by FB23/FB23-2 remarkably suppressed the proliferation and migration of HCC cell lines in vitro, as well as inhibiting the 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 decreased ERBB3 resulted in inhibited Akt-mTOR signaling that subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 abolished the organization of the tubulin cytoskeleton, while enforced expression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrated that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells, and highlights the broad potential of FTO inhibitors for targeting HCC. Overall design: To find the targets of FB23-2 via inhibiting FTO, MHCC97H cells with FB23-2 (2 µM) treatment for 48 h were selected for RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq), DMSO-treated MHCC97H cells as vehicle.