bims-rimeca 2022-07-10 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2022–07–10
twelve papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

The m6A reader YTHDF3-mediated PRDX3 translation alleviates liver fibrosis.
The methyltransferase METTL3 promotes tumorigenesis via mediating HHLA2 mRNA m6A modification in human renal cell carcinoma.
N6-methyladenosine modification and metabolic reprogramming of digestive system malignancies.
ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway.
SHMT2 promotes the tumorigenesis of renal cell carcinoma by regulating the m6A modification of PPAT.
WTAP targets the METTL3 m 6 A-methyltransferase complex to cytoplasmic hepatitis C virus RNA to regulate infection.
FTO knockdown alleviates hypoxia-induced PC12 cell injury by stabilizing GADD45B in an IGF2BP2-dependent manner.
Study on the Correlation Between Regulatory Proteins of N6-methyladenosine and Oxidative Damage in Cadmium-induced Renal Injury.
TTC22 promotes m6A-mediated WTAP expression and colon cancer metastasis in an RPL4 binding-dependent pattern.
Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts.
The methyltransferase METTL3-mediated fatty acid metabolism revealed the mechanism of cinnamaldehyde on alleviating steatosis.
Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis.

Redox Biol. 2022 Jun 24. pii: S2213-2317(22)00150-1. [Epub ahead of print]54 102378

The m6A reader YTHDF3-mediated PRDX3 translation alleviates liver fibrosis.

Ruimin Sun, Xinyao Tian, Yang Li, Yan Zhao, Zhecheng Wang, Yan Hu, Lijun Zhang, Yue Wang, Dongyan Gao, Shusen Zheng, Jihong Yao.

Peroxiredoxin 3 (PRDX3) acts as a master regulator of mitochondrial oxidative stress and exerts hepatoprotective effects, but the role of PRDX3 in liver fibrosis is not well understood. N6-methyladenosine (m6A) is considered the most prevalent posttranscriptional modification of mRNA. This study aimed to elucidate the effect of PRDX3 on liver fibrosis and the potential mechanism through which the m6A modification regulates PRDX3. PRDX3 expression was found to be negatively correlated with liver fibrosis in both animal models and clinical specimens from patients. We performed adeno-associated virus 9 (AAV9)-PRDX3 knockdown and AAV9-PRDX3 HSC-specific overexpression in mice to clarify the role of PRDX3 in liver fibrosis. PRDX3 silencing exacerbated hepatic fibrogenesis and hepatic stellate cell (HSC) activation, whereas HSC-specific PRDX3 overexpression attenuated liver fibrosis. Mechanistically, PRDX3 suppressed HSC activation at least partially via the mitochondrial reactive oxygen species (ROS)/TGF-β1/Smad2/3 pathway. Furthermore, PRDX3 mRNA was modified by m6A and interacted with the m6A readers YTH domain family proteins 1-3 (YTHDF1-3), as evidenced by RNA pull-down/mass spectrometry. More importantly, PRDX3 expression was suppressed when YTHDF3, but not YTHDF1/2, was knocked down. Moreover, PRDX3 translation was directly regulated by YTHDF3 in an m6A-dependent manner and thereby affected its function in liver fibrosis. Collectively, the results indicate that PRDX3 is a crucial regulator of liver fibrosis and that targeting the YTHDF3/PRDX3 axis in HSCs may be a promising therapeutic approach for liver fibrosis.

DOI: https://doi.org/10.1016/j.redox.2022.102378
J Transl Med. 2022 Jul 06. 20(1): 298

The methyltransferase METTL3 promotes tumorigenesis via mediating HHLA2 mRNA m6A modification in human renal cell carcinoma.

Dawei Zhu, Yingting Liu, Junjun Chen, Qi Wang, Yuan Li, Yulan Zhu, Jun Feng, Jingting Jiang.

   BACKGROUND: As an important N6-methyladenosine (m6A) regulator, abnormal expression of methyltransferase-like protein 3 (METTL3) has been reported in certain human cancers. Although some data have shown that METTL3 plays an essential role in the progression of clear-cell renal cell carcinoma RCC (ccRCC), the detailed mechanism still remains largely undetermined.
METHODS: Immunohistochemistry (IHC) assay was used to examine the expression of METTL3 and its clinical implications in human ccRCC by using tissue-microarray (TMA). The cellular models based on ccRCC cell lines such as 786-O and ACHN, were established by operating METTL3 and HHLA2 via knockdown or overexpression, followed by in vitro cellular function studies and in vivo subcutaneous transplantation tumor model.
RESULTS: We found that METTL3 expression in ccRCC tissues was significantly higher compared with adjacent normal tissues. We also found the overall survival (OS) of the patients with low METTL3 expression was significantly better compared with the patients with high METTL3 expression. Furthermore, HHLA2highMETTL3high could serve as a better prognostic predictor for ccRCC patients. Depletion of METTL3 could significantly inhibit the cell viability, migration, and invasion abilities in ccRCC cell lines. Cellular studies further revealed that METTL3 could regulate HHLA2 expression via m6A modification of HHLA2 mRNA. In vitro studies revealed that HHLA2 overexpression could reverse the inhibition of cellular functions mediated by METTL3 depletion. The subcutaneous transplantation tumor model confirmed that HHLA2 overexpression could reverse the inhibition of tumor growth mediated by METTL3 depletion.
CONCLUSION: Our study indicated that METTL3 served as an important prognostic predictor for ccRCC patients, and we demonstrated a novel regulatory mechanism of HHLA2 by mRNA epigenetic modification via METTL3. Moreover, we found that the METTL3/HHLA2 axis could promote tumorigenesis of ccRCC. Collectively, our current findings provided new insights into the therapeutic strategy against this malignancy targeting METTL3.

Keywords:  HHLA2; METTL3; Prognosis; ccRCC; m6A

DOI:  https://doi.org/10.1186/s12967-022-03496-3
Cancer Lett. 2022 Jul 04. pii: S0304-3835(22)00299-3. [Epub ahead of print] 215815

N6-methyladenosine modification and metabolic reprogramming of digestive system malignancies.

Xianlei Cai, Chao Liang, Miaozun Zhang, Yuan Xu, Yihui Weng, Xueying Li, Weiming Yu.

  N6-methyladenosine (m6A) is a eukaryotic post-transcriptional modification involved in cell growth and developmental processes, including RNA transcription, alternative splicing, degradation, and translation. It is also involved in the development of various cancers. Metabolic reprogramming enables cancer cells to obtain nutrition from the tumor microenvironment, which is a hallmark of cancer. Numerous studies have shown that m6A modification induces metabolic reprogramming in cancer by regulating the expression of metabolic core genes or activation of metabolic signaling pathways. Digestive system malignancies include esophageal, gastric, colorectal, liver, pancreatic, and other cancers, all of which are associated with poor outcomes. This review summarizes the role of m6A modification in the metabolic reprogramming of digestive system malignancies, with the aim of identifying therapeutic strategies.

Keywords:  Epigenetic modification; Glucose metabolism; Glutamine metabolism; Lipid metabolism

DOI:  https://doi.org/10.1016/j.canlet.2022.215815
Open Med (Wars). 2022 ;17(1): 1092-1099

ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway.

Xiaoshan Zhang, ShiBing Deng, Yang Peng, Han Wei, Zhiming Tian.

  The dysfunction and apoptosis of vascular endothelial cells are the initiating links in the formation of atherosclerosis. N6-methyladenosine (m6A) is an extremely extensive RNA methylation modification and its abnormality leads to the occurrence of various human diseases. In this study, we explored the effects of demethylase α-ketoglutarate-dependent dioxygenase ALKB homolog 5 (ALKBH5) on TNF-α-induced apoptosis of human umbilical vein endothelial cells (HUVECs). In TNF-α-treated HUVECs, the expression of ALKBH5 was significantly decreased. ALKBH5 overexpression promoted the proliferation and inhibited the apoptosis in TNF-α-treated HUVECs, suggesting that ALKBH5 had a protective effect on cell damage induced by TNF-α. Importantly, ALKBH5 promoted the expression of Bcl-2 in HUVECs. Bcl2 overexpression reduced the expression of Gadd45, Bax, and p21, which are transcriptionally activated by p53. But the expression of p53 has not been significantly affected, indicating that Bcl2 might regulate the apoptosis by inhibiting p53 downstream targets. In addition, ALKBH5 overexpression significantly increased the level of pri-miR-7 and decreased the level of miR-7. In conclusion, ALKBH5 attenuated the TNF-α-induced cell injury via promoting Bcl2 expression. Our research expands the understanding of the progression mechanism of atherosclerosis and provides a potential strategy for the protection of vascular endothelial injury.

Keywords:  ALKBH5; Bcl-2; N6-methyladenosine; apoptosis; atherosclerosis

DOI:  https://doi.org/10.1515/med-2022-0484
Genomics. 2022 Jul 04. pii: S0888-7543(22)00169-0. [Epub ahead of print] 110424

SHMT2 promotes the tumorigenesis of renal cell carcinoma by regulating the m6A modification of PPAT.

Fu-Chun Huo, Min Xie, Zhi-Man Zhu, Jun-Nian Zheng, Dong-Sheng Pei.

   OBJECTIVE: Serine hydroxymethyltransferase 2 (SHMT2) is the first rate-limiting enzyme for serine/glycine biosynthesis and one carbon metabolism. Here, we explore the underlying mechanism of how SHMT2 functions in renal cell carcinoma (RCC) initiation.
METHODS: In this study, SHMT2 expression was assessed in RCC tissues. In vitro experiments were performed to investigate the functional role of SHMT2. The detailed mechanisms of SHMT2-mediated PPAT were addressed.
RESULTS: Increased SHMT2 facilitated RCC cell proliferation by inducing the G1/S phase transition. And SHMT2 promoted the expression of PPAT. Mechanism dissection revealed that SHMT2 enhanced the m6A modification through the endogenous methyl donor SAM mediated by SHMT2 via serine/glycine one carbon metabolic networks. SHMT2-catalyzed serine/glycine conversion regulated PPAT expression in an m6A-IGF2BP2-dependent manner. SHMT2 promoted RCC cell proliferation by upregulating PPAT expression.
CONCLUSIONS: SHMT2 promotes RCC tumorigenesis by increasing PPAT expression. Thus, SHMT2 may be a novel potential therapeutic target for RCC.

Keywords:  Metabolism; N6-methyladenosine; PPAT; Renal cell carcinoma; SHMT2

DOI:  https://doi.org/10.1016/j.ygeno.2022.110424
bioRxiv. 2022 Jun 28. pii: 2022.06.27.497872. [Epub ahead of print]

WTAP targets the METTL3 m 6 A-methyltransferase complex to cytoplasmic hepatitis C virus RNA to regulate infection.

Matthew T Sacco, Katherine M Bland, Stacy M Horner.

Modification of the hepatitis C virus (HCV) positive-strand RNA genome by N6-methyladenosine (m 6 A) regulates the viral lifecycle. This lifecycle takes place solely in the cytoplasm, while m 6 A addition on cellular mRNA takes place in the nucleus. Thus, the mechanisms by which m 6 A is deposited on the viral RNA have been unclear. In this work, we find that m 6 A modification of HCV RNA by the m 6 A-methyltransferase proteins METTL3 and METTL14 is regulated by WTAP. WTAP, a predominantly nuclear protein, is an essential member of the cellular mRNA m 6 A-methyltransferase complex and known to target METTL3 to mRNA. We found that HCV infection induces localization of WTAP to the cytoplasm. Importantly, we found that WTAP is required for both METTL3 interaction with HCV RNA and for m 6 A modification across the viral RNA genome. Further, we found that WTAP, like METTL3 and METTL14, negatively regulates the production of infectious HCV virions, a process that we have previously shown is regulated by m 6 A. Excitingly, WTAP regulation of both HCV RNA m 6 A modification and virion production were independent of its ability to localize to the nucleus. Together, these results reveal that WTAP is critical for HCV RNA m 6 A modification by METTL3 and METTL14 in the cytoplasm.
IMPORTANCE: Positive-strand RNA viruses such as HCV represent a significant global health burden. Previous work has described how HCV RNA contains the RNA modification m 6 A and how this modification regulates viral infection. Yet, how this modification is targeted to HCV RNA has remained unclear due to the incompatibility of the nuclear cellular processes that drive m 6 A modification with the cytoplasmic HCV lifecycle. In this study, we present evidence for how m 6 A modification is targeted to HCV RNA in the cytoplasm by a mechanism in which WTAP recruits the m 6 A-methyltransferase METTL3 to HCV RNA. This targeting strategy for m 6 A modification of cytoplasmic RNA viruses is likely relevant for other m 6 A-modified positive-strand RNA viruses with cytoplasmic lifecycles such as enterovirus 71 and SARS-CoV-2 and provides an exciting new target for potential antiviral therapies.

DOI: https://doi.org/10.1101/2022.06.27.497872
Biochem Biophys Res Commun. 2022 Jun 13. pii: S0006-291X(22)00890-7. [Epub ahead of print]619 166-172

FTO knockdown alleviates hypoxia-induced PC12 cell injury by stabilizing GADD45B in an IGF2BP2-dependent manner.

Dan Wang, Yu Li, Xiaoxiao Xu, Shixin Zhao, Zhen Wang, Jiahao Yang, Xi Zhang, Junwei Pan, Yisheng Wang, Ming Liu.

  RNA N6-methyladenosine (m6A) level is closely associated with neurodevelopment and central nervous system dysfunctions including spinal cord injury (SCI). M6A level can be dynamically regulated by m6A methyltransferases and demethylases. In this text, the roles of m6A demethylase FTO alpha-ketoglutarate dependent dioxygenase (FTO) in SCI development along with its m6A-dependent regulatory mechanisms were investigated in hypoxia-induced PC12 cell injury model. The results showed that FTO was low expressed in spinal cord tissues of rats after contusive SCI and hypoxia-treated PC12 cells. FTO knockdown alleviated hypoxia-induced PC12 cell injury. FTO loss increased GADD45B expression and m6A level in PC12 cells. GADD45B knockdown weakened the protective effects of FTO depletion on hypoxia-treated PC12 cells. FTO regulated GADD45B expression in an IGF2BP2-dependent manner. In conclusion, FTO knockdown mitigated the injury of hypoxia-induced PC12 cells by up-regulating GADD45B in an IGF2BP2-dependent manner.

Keywords:  FTO; GADD45B; IGF2BP2; N6-methyladenosine; Spinal cord injury

DOI:  https://doi.org/10.1016/j.bbrc.2022.06.039
Biol Trace Elem Res. 2022 Jul 06.

Study on the Correlation Between Regulatory Proteins of N6-methyladenosine and Oxidative Damage in Cadmium-induced Renal Injury.

Yifei Sun, Guofen Liu, Mengzhu Li, Lei Wang, Zuoshun He, Shiyan Gu.

  As a common environmental heavy metal pollutant, cadmium has been well evidenced to cause kidney damage; yet, the underlying mechanisms are still not fully clarified. In this study, cell viability of human renal tubular epithelial cell (HK-2) was determined by CCK-8 assay after treatment with CdSO4. Then, apoptotic morphology of cells was observed by Hoechst staining and level of reactive oxygen species (ROS) was detected by fluorescent probes. Subsequently, mRNA levels of Nrf2, HO-1, m6A methyltransferases (METTL3, METTL14, METTL16, WATP), m6A demethylases (FTO, ALKBH5), m6A methyl-binding proteins (YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2) were detected by real-time polymerase chain reaction (RT-PCR), closely followed by correlation analysis between Nrf2 mRNA levels and m6A methyltransferases and demethylases. Lastly, protein expressions of Nrf2, METTL3, and FTO were tested by western blotting assay. The detection results demonstrated that the treatment of CdSO4 decreased viability while increased apoptosis rate. The Nrf2 mRNA level in CdSO4-treated cells was significantly increased when compared with that in the control cells, and the HO-1 mRNA level elevated with the increasing of CdSO4 concentrations. In addition, mRNA levels of METTL3, METTL14, METTL16, WTAP, FTO, and methyl-binding proteins in CdSO4-treated cells were all higher than those in corresponding control cells. Further determination showed that protein expressions of Nrf2, METTL3, and FTO were also upregulation under the treatment of CdSO4. Lastly, correlation analysis indicated that mRNA level of Nrf2 was positively correlated with mRNA levels of m6A methyltransferases and demethylases. In a word, our results demonstrated that the molecular changes of Nrf2 signaling pathway are correlated with the levels of m6A regulatory proteins, suggesting that there may be a regulatory relationship between Nrf2 signaling pathway and m6A regulatory proteins in the process of cadmium-induced renal cell cytotoxicity.

Keywords:  Cadmium sulfate; N6-methyladenosine; Nuclear factor-erythroid 2-related factor 2; Oxidative damage; Renal injury

DOI:  https://doi.org/10.1007/s12011-022-03345-w
Oncogene. 2022 Jul 07.

TTC22 promotes m6A-mediated WTAP expression and colon cancer metastasis in an RPL4 binding-dependent pattern.

Abin You, Wei Tian, Hongfan Yuan, Liankun Gu, Jing Zhou, Dajun Deng.

WTAP, an essential component of the RNA N-6-methyladenosine (m6A) modification complex, guides METLL3-METLL14 heteroduplexes to target RNAs in the nuclear speckles of mammalian cells. Here, we show that TTC22 is widely coexpressed with WTAP and FTO in many human tissues by mining Genotype-Tissue Expression (GTEx) datasets. Our results indicate that the direct interaction of TTC22 with 60S ribosomal protein L4 (RPL4) promotes the binding of WTAP mRNA to RPL4, enhances the stability and translation efficiency of WTAP mRNA, and consequently increases the level of WTAP protein. Also, WTAP mRNA itself is an m6A target and YTHDF1 is characterized as an essential m6A binding protein interacting with m6A-modified WTAP mRNA. TTC22 triggers a positive feedback loop between WTAP expression and WTAP mRNA m6A modification, leading to an increased m6A level in total RNA. The knockdown of RPL4, WTAP, or YTHDF1 expression diminishes the TTC22-induced increase in the m6A level of total RNA. Thus, TTC22 caused dramatic expression changes in genes related to metabolic pathways, ribosomal biogenesis, the RNA spliceosome, and microorganism infections. Importantly, TTC22 upregulates the expression of SNAI1 by increasing m6A level and thus promotes lung metastases of colon cancer cells in mice. In conclusion, our study showed that TTC22 upregulates WTAP and SNAI1 expression, which contributes to TTC22-induced colon cancer metastasis.

DOI: https://doi.org/10.1038/s41388-022-02402-x
Gut. 2022 Jul 08. pii: gutjnl-2022-326928. [Epub ahead of print]

Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts.

Ting Li, Yue-Tao Tan, Yan-Xing Chen, Xiao-Jun Zheng, Wen Wang, Kun Liao, Hai-Yu Mo, Junzhong Lin, Wei Yang, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju.

   OBJECTIVE: Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined.
DESIGN: The antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated.
RESULTS: We found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8+ T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N6-methyladenosine (m6A) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or m6A-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8+ T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients.
CONCLUSIONS: Methionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.

Keywords:  colorectal cancer; immunotherapy; methylation

DOI:  https://doi.org/10.1136/gutjnl-2022-326928
Biomed Pharmacother. 2022 Jun 30. pii: S0753-3322(22)00756-9. [Epub ahead of print]153 113367

The methyltransferase METTL3-mediated fatty acid metabolism revealed the mechanism of cinnamaldehyde on alleviating steatosis.

Ruohui Xu, Xiaoli Xiao, Shengan Zhang, Jiashu Pan, Yingjue Tang, Wenjun Zhou, Guang Ji, Yanqi Dang.

   BACKGROUND: As a primarily N6-methyladenosine methyltransferase, methyltransferase 3 (METTL3) plays a crucial role in nonalcoholic fatty liver disease. However, its regulatory mechanism in steatosis remains unknown.
METHODS: Alpha mouse liver 12 (AML12) cells were induced by free fatty acids (FFA). Triglycerides, lipid droplet assay, and Oil Red O staining were performed to evaluate steatosis. The expression of METTL3 and cytochrome P450 family 4 subfamily f polypeptide 40 (CYP4F40) was measured using Western blotting, real-time quantitative polymerase chain reaction, and dual-luciferase reporter assay. Triglycerides, total cholesterol, almandine aminotransferase, and aspartate aminotransferase were assayed after cinnamaldehyde treatment. Transcriptomics and metabolomics were performed to determine how METTL3 and cinnamaldehyde regulate steatosis.
RESULTS: METTL3 protein level was reduced in FFA-induced steatosis in AML12 cells, and METTL3 knockdown aggravated the steatosis. Cinnamaldehyde alleviated steatosis by increasing METTL3 expression. A combined transcriptomics and metabolomics analysis revealed that METTL3 knockdown reduced CYP4F40 expression and reduced the level of capric acid, gamma-linolenic acid, arachidonic acid, and docosapentaenoic acid. Cinnamaldehyde promoted CYP4F40 expression by increasing METTL3 and increased the levels of capric acid, gamma-linolenic acid, arachidonic acid, and docosapentaenoic acid. Finally, the beneficial effects of cinnamaldehyde on steatosis were reversed after METTL3 knockdown.
CONCLUSIONS: METTL3 knockdown aggravated steatosis in AML12 cells through CYP4F40-mediated fatty acid metabolism, and cinnamaldehyde alleviated steatosis via the METTL3-CYP4F40 pathway.

Keywords:  Cinnamaldehyde; Fatty acids metabolism; METTL3; Steatosis

DOI:  https://doi.org/10.1016/j.biopha.2022.113367
Oncogene. 2022 Jul 07.

Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis.

Qi Meng, Yun-Xin Lu, Chen Wei, Zi-Xian Wang, Jin-Fei Lin, Kun Liao, Xiao-Jing Luo, Kai Yu, Yi Han, Jia-Jun Li, Yue-Tao Tan, Hao Li, Zhao-Lei Zeng, Bo Li, Rui-Hua Xu, Huai-Qiang Ju.

Metastasis accounts for the major cause of cancer-related mortality. How disseminated tumor cells survive under suspension conditions and avoid anoikis is largely unknown. Here, using a metabolic enzyme-centered CRISPR-Cas9 genetic screen, we identified methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1) as a novel suppressor of anoikis. MTHFD1 depletion obviously restrained the capacity of cellular antioxidant defense and inhibited tumor distant metastasis. Mechanistically, MTHFD1 was found to bind the protein arginine methyltransferase 5 (PRMT5) and then undergo symmetric dimethylation on R173 by PRMT5. Under suspension conditions, the interaction between MTHFD1 and PRMT5 was strengthened, which increased the symmetric dimethylation of MTHFD1. The elevated methylation of MTHFD1 largely augmented its metabolic activity to generate NADPH, therefore leading to anoikis resistance and distant organ metastasis. Therapeutically, genetic depletion or pharmacological inhibition of PRMT5 declined tumor distant metastasis. And R173 symmetric dimethylation status was associated with metastasis and prognosis of ESCC patients. In conclusion, our study uncovered a novel regulatory role and therapeutic implications of PRMT5/MTHFD1 axis in facilitating anoikis resistance and cancer metastasis.

DOI: https://doi.org/10.1038/s41388-022-02387-7