Research Paper|Volume 15, Issue 18|pp 9590—9613

YY1 is regulated by ALKBH5-mediated m6A modification and promotes autophagy and cancer progression through targeting ATG4B

Shijiang Wang^1,^2,³, Jiangbo Nie^1,^2,³, Kaiying Xu^2,⁴, Yangyang Liu^2,⁵, Weilai Tong^1,^2,³, Anan Li^1,^2,³, Wei Zuo^1,^2,³, Zhili Liu^1,^2,³, Feng Yang^1,^2,^3,⁶

¹Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China
²Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China
³Institute of Spine and Spinal Cord, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China
⁴Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China
⁵Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China
⁶Postdoctoral Innovation Practice Base, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China

* Equal contribution and co-first authors

Received: May 30, 2023Accepted: August 29, 2023Published: September 18, 2023

https://doi.org/10.18632/aging.205037

Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

YY1 affects tumorigenesis and metastasis in multiple ways. However, the function of YY1 and the potential mechanisms through which it operates in gastric cancer (GC) progression by regulating autophagy remains poorly understood. This study aimed to assess the essential transcription factors (TFs) involved in autophagy regulation in GC. Western blot, RFP-GFP-LC3 double fluorescence and transmission electron microscopy (TEM) assays were used to probe autophagy activity in GC cells. Methylated RNA immunoprecipitation (MeRIP) was utilized to evaluate the ALKBH5-regulated m6A levels of YY1. Gain- and loss-of-function assays were employed in the scrutiny of the biological effects of the ALKBH5/YY1/ATG4B axis on cancer cell proliferation and invasion abilities in vitro. Per the findings, YY1 was identified as a crucial transcriptional activator of cancer autophagy-related genes and promoted the proliferation and aggressiveness of cancer cells associated with enhanced ATG4B-mediated autophagy. However, ectopic ALKBH5 expression abolished the YY1-induced effect via m6A modification. Importantly, YTHDF1 facilitated the mRNA stability of YY1 through m6A recognition. Collectively, this study found that YY1 was regulated by ALKBH5 and YTHDF1-mediated m6A modification and served as an autophagy-dependent tumor driver to accelerate cancer progression through ATG4B transactivation, providing an exploitable therapeutic target for GC.