YAP-activated NAT10 promotes hepatoblastoma progression by activating the pentose phosphate pathway

Hepatoblastoma (HB) is the most common malignant liver tumor in children, with limited treatment options. The N4-acetylcytidine (ac4C) modification, an important mRNA post-transcriptional modification catalyzed by N-acetyltransferase 10 (NAT10), plays a crucial role in the initiation and progression of tumors. However, its impact on the development and prognosis of HB is largely unknown. This study demonstrates that NAT10 is notably upregulated in HB. NAT10 inhibition suppressed HB proliferation and metastasis <i>in vitro</i> and <i>in vivo</i>. Mechanistically, Yes-associated protein 1 (YAP1) induced NAT10 transcription by binding to its promoter, which stimulates the ac4C modification within the 3' untranslated region (3' UTR) of glucose-6-phosphate dehydrogenase (G6PD) and enhancing its mRNA stability. YAP1/NAT10/G6PD axis resulted in enhanced pentose phosphate pathway (PPP) to promote proliferation and metastasis of HB. Moreover, said NAT10-mediated oncogenic effect could be significantly attenuated by a NAT10 inhibitor (Remodelin) both <i>in vitro</i> experiments and <i>in vivo</i> HB mouse models. Overall, our findings revealed the oncogenic role of NAT10 in regulating HB growth and metastasis, which can be a potential therapeutic target for human HB.