Linking the YTH domain to cancer: the importance of YTH family proteins in epigenetics

Shi, Rongkai; Ying, Shilong; Li, Yadan; Zhu, Liyuan; Wang, Xian; Jin, Hongchuan

doi:10.1038/s41419-021-03625-8

Cited by 51 publications

(41 citation statements)

References 135 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The above results show that METTL3 regulates SLC7A11 expression to promote LUAD, yet the modification mechanism remains to be elucidated. YTHDF1 is recognized as one of the most important m 6 A readers responsible for mRNA translation [ 26 ]. Recent studies inspired us that METTL3 could recruit YTHDF1 to promote their target transcript stability [ 27 , 28 ].…”

Section: Resultsmentioning

confidence: 99%

METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification

Yan

et al. 2022

Cancer Cell Int

View full text Add to dashboard Cite

Background N6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m6A, in LUAD progression. Methods The expression of m6A, METTL3, YTHDF1 and SLC7A11 were detected by immunochemistry or/and online datasets in LUAD patients. The effects of METTL3 on LUAD cell proliferation, apoptosis and ferroptosis were assessed through in vitro loss-and gain-of-function experiments. The in vivo effect on tumorigenesis of METTL3 was evaluated using the LUAD cell xenograft mouse model. MeRIP-seq, RNA immunoprecipitation and RNA stability assay were conducted to explore the molecular mechanism of METTL3 in LUAD. Results The results showed that the m6A level, as well as the methylase METTL3 were both significantly elevated in LUAD patients and lung cancer cells. Functionally, we found that METTL3 could promote proliferation and inhibit ferroptosis in different LUAD cell models, while METTL3 knockdown suppressed LUAD growth in cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), the subunit of system Xc−, was identified as the direct target of METTL3 by mRNA-seq and MeRIP-seq. METTL3-mediated m6A modification could stabilize SLC7A11 mRNA and promote its translation, thus promoting LUAD cell proliferation and inhibiting cell ferroptosis, a novel form of programmed cell death. Additionally, we demonstrated that YTHDF1, a m6A reader, was recruited by METTL3 to enhance SLC7A11 m6A modification. Moreover, the expression of YTHDF1 and SLC7A11 were positively correlated with METTL3 and m6A in LUAD tissues. Conclusions These findings reinforced the oncogenic role of METTL3 in LUAD progression and revealed its underlying correlation with cancer cell ferroptosis; these findings also indicate that METTL3 is a promising novel target in LUAD diagnosis and therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification

Yan

et al. 2022

Cancer Cell Int

View full text Add to dashboard Cite

show abstract

“…m 6 A binding protein, known as “reader”, is capable of decoding m 6 A methylation and yielding a series of functional signals, mainly including YTH domain containing protein, IGF2BP and HNRNP families [ 8 , 9 ]. YTH domain can recognize m 6 A via a conserved aromatic cage [10] , thus regulating RNA transcription, splicing, processing, stability and translation [ 11 , 12 ]. YTH domain containing 2 (YTHDC2), the final member of the YTH protein family, has recently been reported as a key regulator in several human diseases [13] .…”

Section: Introductionmentioning

confidence: 99%

The N6-methyladenosine reader protein YTHDC2 promotes gastric cancer progression via enhancing YAP mRNA translation

Wang

Chen

et al. 2022

Translational Oncology

View full text Add to dashboard Cite

Highlights YTHDC2 is significantly upregulated in human GC tissues, which is linked to poor prognosis. Knockout of YTHDC2 inhibits GC cell proliferation, migration and invasion. YTHDC2 enhances YAP translation in a m 6 A-dependent manner. YAP transcriptionally activates YTHDC2. Knockout of YTHDC2 inhibits GC tumor growth and metastasis in vivo .

show abstract

“…We have to emphasize that although TLS/FUS does not contain a YTH domain, which is regarded as an essential domain for m 6 A recognition [40,41], either WT or mutated TLS/FUS strongly bound to m 6 A-modified RNA fragments. In the previous paper, we inferred that TLS/FUS could be an m 6 A reader protein [30], and to the best of our knowledge, this is the first report describing the TLS/FUS binding specificity to m 6 A-modified RNAs.…”

Section: Discussionmentioning

confidence: 97%

m6A Modified Short RNA Fragments Inhibit Cytoplasmic TLS/FUS Aggregation Induced by Hyperosmotic Stress

Yoneda

Ueda

Kurokawa

2021

IJMS

View full text Add to dashboard Cite

Translocated in LipoSarcoma/Fused in Sarcoma (TLS/FUS) is a nuclear RNA binding protein whose mutations cause amyotrophic lateral sclerosis. TLS/FUS undergoes LLPS and forms membraneless particles with other proteins and nucleic acids. Interaction with RNA alters conformation of TLS/FUS, which affects binding with proteins, but the effect of m6A RNA modification on the TLS/FUS–RNA interaction remains elusive. Here, we investigated the binding specificity of TLS/FUS to m6A RNA fragments by RNA pull down assay, and elucidated that both wild type and ALS-related TLS/FUS mutants strongly bound to m6A modified RNAs. TLS/FUS formed cytoplasmic foci by treating hyperosmotic stress, but the cells transfected with m6A-modified RNAs had a smaller number of foci. Moreover, m6A-modified RNA transfection resulted in the cells obtaining higher resistance to the stress. In summary, we propose TLS/FUS as a novel candidate of m6A recognition protein, and m6A-modified RNA fragments diffuse cytoplasmic TLS/FUS foci and thereby enhance cell viability.

show abstract

Linking the YTH domain to cancer: the importance of YTH family proteins in epigenetics

Cited by 51 publications

References 135 publications

METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification

METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification

The N6-methyladenosine reader protein YTHDC2 promotes gastric cancer progression via enhancing YAP mRNA translation

m6A Modified Short RNA Fragments Inhibit Cytoplasmic TLS/FUS Aggregation Induced by Hyperosmotic Stress

Contact Info

Product

Resources

About