Loss of RDM1 enhances hepatocellular carcinoma progression via p53 and Ras/Raf/ERK pathways

Chen, Shi-Lu; Liu, Li‐Li; Wang, Chunhua; Lu, Shi-Xun; Yang, Xia; He, Yangfan; Zhang, Chris Zhiyi; Yun, Jing‐Ping

doi:10.1002/1878-0261.12593

Cited by 48 publications

(45 citation statements)

References 43 publications

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“… Oncogene Acute myeloid leukemia MYC , BCL2 , PTEN Promote translation Differentiation, apoptosis [ 73 ] CEBPZ SP1 , SP2 Promote translation Cell cycle regulation, differentiation [ 74 ] Breast cancer let-7g HBXIP Promote translation (?) Cell proliferation [ 63 ] BCL2 Promote translation Proliferation, apoptosis [ 75 ] Liver cancer SOCS2 RNA decay by YTHDF2 Proliferation, migration [ 76 ] RDM1 Proliferation [ 77 ] LINC00958 RNA stabilization Lipogenesis, proliferation, migration, invasion [ 78 ] SUMO1 Snail RNA stabilization Metastasis [ 79 ] Snail promote translation by YTHDF1 EMT [ 80 ] miR24-2 miR-6097 , Pim1 Tumor growth [ 59 ] CTNNB1 RNA stabilization Tumor growth [ 81 ] miR-186 Wnt/β-catenin Proliferation, migration, invasion [ 60 ] Glioblastoma SOX2 RNA stabilization by ELAVL1 Dedifferentiation [ …”

Section: Mettl3 Functions As An M 6 a Methyltransfmentioning

confidence: 99%

Roles of METTL3 in cancer: mechanisms and therapeutic targeting

et al. 2020

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N 6-methyladenosine (m 6 A) is the most abundant mRNA modification and is catalyzed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. Accumulating evidence in recent years reveals that METTL3 plays key roles in a variety of cancer types, either dependent or independent on its m 6 A RNA methyltransferase activity. While the roles of m 6 A modifications in cancer have been extensively reviewed elsewhere, the critical functions of METTL3 in various types of cancer, as well as the potential targeting of METTL3 as cancer treatment, have not yet been highlighted. Here we summarize our current understanding both on the oncogenic and tumor-suppressive functions of METTL3, as well as the underlying molecular mechanisms. The welldocumented protein structure of the METTL3/METTL14 heterodimer provides the basis for potential therapeutic targeting, which is also discussed in this review.

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Section: Mettl3 Functions As An M 6 a Methyltransfmentioning

confidence: 99%

Roles of METTL3 in cancer: mechanisms and therapeutic targeting

et al. 2020

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“…Our study first indicated that BATF2 binds to p53 and attenuates its ubiquitination-mediated degradation. Furthermore, it has been reported that p53 can regulate ERK signaling in various cancers [ 25 – 27 ]. Here, we proved that BATF2 interacted with p53, which consequently inhibited the activation of ERK signaling.…”

Section: Discussionmentioning

confidence: 99%

m6A modification-mediated BATF2 acts as a tumor suppressor in gastric cancer through inhibition of ERK signaling

et al. 2020

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Background: BATF2, also known as SARI, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Methods: We obtained GC tissues and corresponding normal tissues from 8 patients and identified BATF2 as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine BATF2 levels in normal and GC tissues. The prognostic value of BATF2 was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of BATF2 in GC growth and metastasis were evaluated in vitro and in vivo. Results: BATF2 expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that BATF2 was an independent prognostic factor and effective predictor in patients with GC. Low BATF2 expression was remarkably associated with peritoneal recurrence after curative gastrectomy. Moreover, elevated BATF2 expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, BATF2 binds to p53 and enhances its protein stability, thereby inhibiting the phosphorylation of ERK. Tissue microarray results indicated that the prognostic value of BATF2 was dependent on ERK activity. In addition, the N6-methyladenosine (m 6 A) modification of BATF2 mRNA by METTL3 repressed its expression in GC. Conclusions: Collectively, our findings indicate the pivotal role of BATF2 in GC and highlight the regulatory function of the METTL3/BATF2/p53/ERK axis in modulating GC progression, which provides potential prognostic and therapeutic targets for GC treatment.

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“…suppressed HCC cells proliferation by targeting p53 [23] . Transcriptometric sequencing assay screened a set of GRSF1 target RNAs, and YY1 was identi ed for further analysis due to its protumorigenic role in HCC.…”

Section: Discussionmentioning

confidence: 99%

The Rna-binding Protein GRSF1 Promote shepatocarcinogenesis via competitively Binding Toyy1 mRNA with mIR-30e-5p

Han

Wang

et al. 2020

Preprint

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Background:Numerous studies have highlighted that dysregulation of RNA binding protein (RBP) expression is causally linked with human cancer tumorigenesis. The detailed biological effect and underlying mechanisms of RBP GRSF1 in hepatocellular carcinoma (HCC) remain unclear.Methods:GRSF1 expression in HCC tissues and cells was measured by western blotting and qRT-PCR assays. HCC cells with stable knockdown of GRSF1 were established using two sh-RNA encoding lentiviruses. Then the functions of GRSF1 in HCC were explored using MTT, colony formation, flow cytometry, Transwell assays and xenograft model. Transcriptometric sequencing in GRSF1-deficient MHCC-97H cells were carried out to identify the downstream effector of GSRF1. The regulatory mechanisms among GRSF1, YY1 and miR-30e-5p were investigated by RNA immunoprecipitation, luciferase assay, RNA pull down and ChIP assay.Results:GRSF1was frequently increased in HCC tissue and cells with a worse clinical outcomes in HCC. GRSF1 worked as a novel oncogenic RBP in vitro and in vivo via post-regulating the stability of YY1 mRNA. And the GUUU motifs on YY1 3`UTR 2663-2847 was the specific binding motifs for GRSF1. More interesting, YY1 feedback promoted GRSF1 expression by binding to GRSF1 promoters. In addition, YY1 was a critical target of miR-30e-5p, which was confirmed by our data that inhibited HCC hepatocarcinogenesis. Further investigation showed GRSF1 and miR-30e-5p competitively regulated YY1 via binding to its YY1 3`UTR 2663-2847 region. At last, we identified that 3-amino-6-(4-methylsulfonylphenyl)-N-phenylpyrazine-2-carboxamide (VE821) blocked HCC progression by inhibiting the GRSF1/YY1 pathway.Conclusions:GRSF1 promoted hepatocarcinogenesis via competitively binding to YY1 3`UTR 2663-2847 with miR-30e-5p.The interaction network among GRSF1, YY1 and miR-30e-5p provided a new insight for the HCC pathogenesis, and VE821 may serve as a novel agent with potential for HCC treatment via inhibiting GRSF1/YY1 axis.

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Loss of RDM1 enhances hepatocellular carcinoma progression via p53 and Ras/Raf/ERK pathways

Cited by 48 publications

References 43 publications

Roles of METTL3 in cancer: mechanisms and therapeutic targeting

Roles of METTL3 in cancer: mechanisms and therapeutic targeting

m6A modification-mediated BATF2 acts as a tumor suppressor in gastric cancer through inhibition of ERK signaling

The Rna-binding Protein GRSF1 Promote shepatocarcinogenesis via competitively Binding Toyy1 mRNA with mIR-30e-5p

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