Abstract

N6-methyladenosine (m6A), and its reader protein YTHDF1, play a pivotal role in human tumorigenesis by affecting nearly every stage of RNA metabolism. Autophagy activation is one of the ways by which cancer cells survive hypoxia. However, the possible involvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma (HCC). In this study, specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing, -knockout, and -knockdown HCC cells, HCC organoids, and HCC patient-derived xenograft (PDX) murine models. YTHDF1 expression and hypoxia-induced autophagy were significantly correlated in vitro; significant overexpression of YTHDF1 in HCC tissues was associated with poor prognosis. Multivariate cox regression analysis identified YTHDF1 expression as an independent prognostic factor in patients with HCC. Multiple HCC models confirmed that YTHDF1 deficiency inhibited HCC autophagy, growth, and metastasis. Luciferase reporter assays and chromatin immunoprecipitation demonstrated that HIF-1α regulated YTHDF1 transcription by directly binding to its promoter region under hypoxia. The results of methylated RNA immunoprecipitation sequencing, proteomics, and polysome profiling indicated that YTHDF1 contributed to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modified ATG2A and ATG14 mRNA, thus facilitating autophagy and autophagy-related malignancy of HCC. Taken together, HIF-1α-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner. Our findings suggest that YTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC.

Highlights

  • Hepatocellular carcinoma (HCC) is one of the most prevalent lethal tumors, with Chinese HCC patients accounting for 50% of global cases.[1,2] Despite the tremendous progress in HCC treatment, therapeutic options remain limited.[3,4] Only a small proportion of patients with HCC are eligible for curative treatments such as surgical resection, ablation, and liver transplantation

  • Autophagic flux in the HCC cell lines were determined (Supple-we evaluated the oncogenic role of YTHDF1 in human mentary Table S1), revealing that transcription of YTHDF1 was HCC hypoxia-induced autophagy and autophagy-related HCC mostly correlated with autophagosome formation under hypoxic malignancy using multiple models, including HCC cells, HCC conditions (Fig. 1a, b and Supplementary Fig. S1a–c)

  • Considering that hypoxia upregulated YTHDF1 expression in a Hypoxia-inducible factors (HIFs)-1α-dependent manner, we focused on the role of YTHDF1 in HCC cells under hypoxic conditions, which is more similar to the microenvironment in solid tumors

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Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most prevalent lethal tumors, with Chinese HCC patients accounting for 50% of global cases.[1,2] Despite the tremendous progress in HCC treatment, therapeutic options remain limited.[3,4] Only a small proportion of patients with HCC are eligible for curative treatments such as surgical resection, ablation, and liver transplantation. The majority of patients with HCC demonstrate postsurgical recurrence and metastasis, resulting in a poor 5-year overall survival rate.[5] new therapeutic strategies are required to address these limitations. Rapid growth, accompanied by insufficient blood supply, causes a hypoxic microenvironment in solid tumors,[6,7] forcing tumor cells to adapt to hypoxic stress through invasion and metastasis

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