METTL3 Inhibits Antitumor Immunity by Targeting m6A-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer

Chen, Huarong; Pan, Yasi; Zhou, Qiming; Liang, Cong; Wong, Chi-Chun; Zhou, Yunfei; Huang, Dan; Liu, Weixin; Zhai, Jianning; Gou, Hongyan; Su, Hao; Zhang, Xiaoting; Xu, Hui; Wang, Yifei; Kang, Wei; Wu, William Ka Kei; Yu, Jun

doi:10.1053/j.gastro.2022.06.024

Cited by 139 publications

(97 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…m6A modification could shape the CRC immune microenvironment. We demonstrated that high METTL3 expression in CRC cells induced the m6A-BHLHE41-CXCL1 axis to promote the infiltration of myeloid-derived suppressor cells (MDSCs) in the CRC microenvironment, and that the loss of METTL3 in CRC compromised its ability to drive MDSC accumulation and suppressive potency, resulting in enhanced anti-tumor immune responses and diminished CRC growth [ 77 ]. In line with our study, a loss of METTL3 or METTL14 in CRC was reported to promote IFN-γ-Stat1-Irf1-signaling in an m6A-dependent manner to regulate anti-tumor immune responses upon anti-PD-1 therapy [ 78 ].…”

Section: The Role Of Rna Modification In Gi Cancermentioning

confidence: 99%

“…It is worth noting that the inhibitory effect of UZH1a against METTL3 activity is reported to last for at least 6 days [ 100 ]. STM2457 is another newly identified METTL3 inhibitor through a high-throughput screen of 250,000 diverse drug-like compounds [ 77 ]. STM2457 could selectively bind to the SAM site of METTL3 to suppress m6A catalytic activity with a half-maximal inhibitory concentration (IC50) of 16.9 nM [ 77 ].…”

Section: Targeting Rna Modification In Cancermentioning

confidence: 99%

“…STM2457 is another newly identified METTL3 inhibitor through a high-throughput screen of 250,000 diverse drug-like compounds [ 77 ]. STM2457 could selectively bind to the SAM site of METTL3 to suppress m6A catalytic activity with a half-maximal inhibitory concentration (IC50) of 16.9 nM [ 77 ]. Remarkably, the administration of STM2457 impaired acute myeloid leukemia (AML) growth and prolonged mouse survival in various mouse models of AML [ 101 ].…”

Section: Targeting Rna Modification In Cancermentioning

confidence: 99%

“…Targeting m6A regulators has shed new light to improve the effectiveness of cancer immune checkpoint inhibitor (ICI). Our recent study demonstrated that the targeting of METTL3 by METTL3-sgRNA or chemical METTL3 inhibitor STM2457 could potentiate the effect of anti-PD1 treatment in different mouse CRC syngeneic models [ 77 ]. Mechanistically, the targeting of METTL3 suppressed MDSC infiltration in a CRC microenvironment, which unleashed an anti-PD1-mediated CD8+ T cell antitumor response [ 77 ].…”

Section: Targeting Rna Modification In Cancermentioning

confidence: 99%

“…Our recent study demonstrated that the targeting of METTL3 by METTL3-sgRNA or chemical METTL3 inhibitor STM2457 could potentiate the effect of anti-PD1 treatment in different mouse CRC syngeneic models [ 77 ]. Mechanistically, the targeting of METTL3 suppressed MDSC infiltration in a CRC microenvironment, which unleashed an anti-PD1-mediated CD8+ T cell antitumor response [ 77 ]. In line with our findings, Wang et al, reported that CRC cells with METTL3 or METTL14 knockout were more sensitive to anti-PD-1 treatment [ 78 ].…”

Section: Targeting Rna Modification In Cancermentioning

confidence: 99%

See 4 more Smart Citations

RNA Modifications in Gastrointestinal Cancer: Current Status and Future Perspectives

Zhang

Chen

et al. 2022

Biomedicines

Self Cite

View full text Add to dashboard Cite

Gastrointestinal (GI) cancer, referring to cancers of the digestive system such as colorectal cancer (CRC), gastric cancer (GC), and liver cancer, is a major cause of cancer-related deaths in the world. A series of genetic, epigenetic, and epitranscriptomic changes occur during the development of GI cancer. The identification of these molecular events provides potential diagnostic, prognostic, and therapeutic targets for cancer patients. RNA modification is required in the posttranscriptional regulation of RNA metabolism, including splicing, intracellular transport, degradation, and translation. RNA modifications such as N6-methyladenosine (m6A) and N1-methyladenosine (m1A) are dynamically regulated by three different types of regulators named methyltransferases (writers), RNA binding proteins (readers), and demethylases (erasers). Recent studies have pointed out that abnormal RNA modification contributes to GI tumorigenesis and progression. In this review, we summarize the latest findings on the functional significance of RNA modification in GI cancer and discuss the therapeutic potential of epitranscriptomic inhibitors for cancer treatment.

show abstract

Section: The Role Of Rna Modification In Gi Cancermentioning

confidence: 99%

Section: Targeting Rna Modification In Cancermentioning

confidence: 99%

Section: Targeting Rna Modification In Cancermentioning

confidence: 99%

Section: Targeting Rna Modification In Cancermentioning

confidence: 99%

Section: Targeting Rna Modification In Cancermentioning

confidence: 99%

See 3 more Smart Citations

RNA Modifications in Gastrointestinal Cancer: Current Status and Future Perspectives

Zhang

Chen

et al. 2022

Biomedicines

Self Cite

View full text Add to dashboard Cite

show abstract

RNA N⁶‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer

Jang,

Hwa,

Kim

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon‐γ (IFN‐γ) signaling, in which IFN‐γ is linked to improved responsiveness to ICIs. Herein, the roles of RNA N6‐methyladenosine (m6A) modifications in regulation of IFN‐γ signaling and the responsiveness to ICIs are unveiled. The m6A‐binding protein YTH N6‐methyladenosine RNA‐binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN‐γ in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN‐γ responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN‐γ signaling, leading to reduced RNA stability and consequent downregulation of IFN‐γ signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor‐infiltrating lymphocytes, which are attributed to the augmentation of IFN‐γ signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN‐γ signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.

show abstract

Peptide Degrader‐Based Targeting of METTL3/14 Improves Immunotherapy Response in Cutaneous Melanoma

Han,

Li,

Feng

et al. 2024

Angewandte Chemie

View full text Add to dashboard Cite

METTL3 has emerged as a promising therapeutic target in cancer treatment, although its oncogenic functions in melanoma development and potential for therapeutic targeting drug have not been fully explored. In this study, we define the oncogenic role of METTL3 in melanoma development and progression. Building on this insight, we examine our recently designed peptide inhibitor RM3, which targets the binding interface of METTL3/14 complex for disruption and subsequent ubiquitin‐mediated proteasomal degradation via the E3 ligase STUB1. RM3 treatment reduces proliferation, migration, and invasion, and induces apoptosis in melanoma cells in vitro and in vivo. Subsequent transcriptomic analysis identified changes in immuno‐related genes following RM3‐mediated suppression of METTL3/14 N6‐methyladenosine (m6A) methyltransferase activity, suggesting a potential for interaction with immunotherapy. A combination treatment of RM3 with anti‐PD‐1 antibody results in significantly higher beneficial tumor response in vivo, with a good safety profile. Collectively, these findings not only delineate the oncogenic role of METTL3 in melanoma but also showcase RM3, acting as a peptide degrader, as a novel and promising strategy for melanoma treatment.

show abstract

METTL3 Inhibits Antitumor Immunity by Targeting m6A-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer

Cited by 139 publications

References 32 publications

RNA Modifications in Gastrointestinal Cancer: Current Status and Future Perspectives

RNA Modifications in Gastrointestinal Cancer: Current Status and Future Perspectives

RNA N⁶‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer

Peptide Degrader‐Based Targeting of METTL3/14 Improves Immunotherapy Response in Cutaneous Melanoma

Contact Info

Product

Resources

About

METTL3 Inhibits Antitumor Immunity by Targeting m6A-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer

Cited by 139 publications

References 32 publications

RNA Modifications in Gastrointestinal Cancer: Current Status and Future Perspectives

RNA Modifications in Gastrointestinal Cancer: Current Status and Future Perspectives

RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer

Peptide Degrader‐Based Targeting of METTL3/14 Improves Immunotherapy Response in Cutaneous Melanoma

Contact Info

Product

Resources

About

RNA N⁶‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer