Aging
Navigate
Submit an Article
Research Paper|Volume 15, Issue 16|pp 8444—8457

m6A methyltransferase METTL16 mediates immune evasion of colorectal cancer cells via epigenetically regulating PD-L1 expression

Ailei Wang1, Yingjie Sun1, Xince Wang1, Zhaofei Yan1, Dongsheng Wang1, Li Zeng1, Qingge Lu2
  • 1Department of Anorectal, Tangshan Traditional Chinese Medicine Hospital, Tangshan, China
  • 2Tangshan Traditional Chinese Medicine Hospital, Tangshan, China
* Equal contribution
Received: March 11, 2023Accepted: July 24, 2023Published: August 29, 2023
https://doi.org/10.18632/aging.204980

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

Background: The immune checkpoint inhibitors (ICIs) has dramatically changed the therapeutic area of cancers. A great number of patients with CRC exhibit poor response rate to ICI treatment. N6-methyl adenosine (m6A) is closely correlated with the initiation and progression of cancers. To explore the role of methyltransferase-like 16 (METTL16) in CRC treatment.

Methods: Clinical samples and different CRC cell lines were collected. The expression of METTL16 and PD-L1 was determined by qPCR, IHC. Ectopic expression of METTL16 was performed in CRC cells. A co-culture system was established using CRC cells and T cells to measure the immune evasion. Cell viability, apoptosis, migration, and invasion were examined by CCK-8, colony formation, flow cytometry, Transwell, and wound healing assay, respectively. The N6-methyl adenosine (m6A) modification of PD-L1 by METTL16 was investigated by methylated RIP (MeRIP) and RNA stability experiment. In vivo xenograft model was established to measure the effects of METTL16 on CRC growth.

Results: METTL16 was decreased and PD-L1 was increased in CRC tissues and cell lines. METTL16 enhanced cell proliferation, migration, and invasion, and promoted CRC tumor growth in vivo. METTL16 induced m6A modification and decreased the stability of METTL16 RNA, leading to the suppression of METTL16 level. METTL16 overexpression in CRC cells induced decreased portion of PD-1 positive T cells. Overexpression of METTL16 and inhibition of PD-1 synergistically suppressed in vivo growth of CRC cells.

Conclusions: Our work identified the METTL16/PD-L1/PD-1 regulatory axis in CRC development and immune evasion, which represented a promising target for CRC treatment.