LncRNA MNX1-AS1 sustains inactivation of Hippo pathway through a positive feedback loop with USP16/IGF2BP3 axis in gallbladder cancer

Liu, Shilei; Li, Huaifeng; Zhu, Yi; Ma, Xiaoming; Shao, Ziyu; Yang, Ziyi; Cai, Chen; Wu, Zhihua; Li, Maolan; Gong, Wei; Wu, Xiangsong

doi:10.1016/j.canlet.2022.215862

Cited by 23 publications

(15 citation statements)

References 47 publications

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“…In addition, STRIP2 upregulated IGF2BP3 transcription and protein levels, thus leading to formulate a STRIP2-IGF2BP3 positive loop in NSCLC progression. IGF2BP3 was considered as an m6A reader and contributed to tumor progression through mediating the stabilization of IGF2BP3 targets in an m6Adependent manner [35,46,47]. Our finding supports that STRIP2-IGF2BP3 axis stabilizes the TMBIM6 level in an m6A-dependent manner.…”

Section: Discussionsupporting

confidence: 82%

STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent

Zhang

Chen

et al. 2023

J Exp Clin Cancer Res

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Background Striatin interacting protein 2 (STRIP2) is a core component of the striatin-interacting phosphatase and kinase (STRIPAK) complexes, which is involved in tumor initiation and progression via the regulation of cell contractile and metastasis. However, the underlying molecular mechanisms of STRIP2 in non-small cell lung cancer (NSCLC) progression remain largely unknown. Methods The expressions of STRIP2 and IGF2BP3 in human NSCLC specimens and NSCLC cell lines were detected using quantitative RT-PCR, western blotting, and immunohistochemistry (IHC) analyses. The roles and molecular mechanisms of STRIP2 in promoting NSCLC progression were investigated in vitro and in vivo. Results Here, we found that STRIP2 expression was significantly elevated in NSCLC tissues and high STRIP2 expression was associated with a poor prognosis. Knockdown of STRIP2 suppressed tumor growth and metastasis in vitro and in vivo, while STRIP2 overexpression obtained the opposite effect. Mechanistically, P300/CBP-mediated H3K27 acetylation activation in the promoter of STRIP2 induced STRIP2 transcription, which interacted with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and upregulated IGF2BP3 transcription. In addition, STRIP2-IGF2BP3 axis stimulated m6A modification of TMBIM6 mRNA and enhanced TMBIM6 stability. Consequently, TMBIM6 involved NSCLC cell proliferation, migration and invasion dependent on STRIP2 and IGF2BP3. In NSCLC patients, high co-expression of STRIP2, IGF2BP3 and TMBIM6 was associated with poor outcomes. Conclusions Our findings indicate that STRIP2 interacts with IGF2BP3 to regulate TMBIM6 mRNA stability in an m6A-dependent manner and may represent a potential prognostic biomarker and therapeutic target for NSCLC.

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Section: Discussionsupporting

confidence: 82%

STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent

Zhang

Chen

et al. 2023

J Exp Clin Cancer Res

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“…MNX1-AS1 has been implicated in many cancer types, including gastric cancer, colorectal cancer, and cholangiocarcinoma [ 61 ]. To address the role of MNX1-AS1 in gallbladder cancer, it was found to enhance the binding of IGF2BP3 (Insulin-like growing factor 2 mRNA-binding protein 3) to USP16 [ 48 ] ( Figure 4 H). USP16 then deubiquitinates poly-ubiquitinated IGF2BP3 and protects it from proteasome-dependent degradation.…”

Section: The Substrates and Functions Of Usp16mentioning

confidence: 99%

“…USP16 then deubiquitinates poly-ubiquitinated IGF2BP3 and protects it from proteasome-dependent degradation. Thus, USP16 stabilizes IGF2BP3, which may be the partial mechanism of MNX1-AS1 -driven gallbladder cancer [ 48 ] ( Figure 4 H).…”

Section: The Substrates and Functions Of Usp16mentioning

confidence: 99%

The Pleiotropic Ubiquitin-Specific Peptidase 16 and Its Many Substrates

Zheng

Chen

Guo

et al. 2023

Cells

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Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions. It was originally identified as the major deubiquitinase for histone H2A and has since been found to deubiquitinate a range of other substrates, including proteins from both the cytoplasm and nucleus. USP16 is phosphorylated when cells enter mitosis and dephosphorylated during the metaphase/anaphase transition. While much of USP16 is localized in the cytoplasm, separating the enzyme from its substrates is considered an important regulatory mechanism. Some of the functions that USP16 has been linked to include DNA damage repair, immune disease, tumorigenesis, protein synthesis, coronary artery health, and male infertility. The strong connection to immune response and the fact that multiple oncogene products are substrates of USP16 suggests that USP16 may be a potential therapeutic target for the treatment of certain human diseases.

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“…MNX1-AS1 has previously attracted the attention of researchers with different studies showing it is overexpressed in a variety of malignancies including colorectal cancer, cervical cancer, ovarian cancer, prostate cancer, breast cancer, esophageal cancer (ESCC), laryngeal squamous cell carcinoma (LSCC), lung cancer, gall bladder cancer (GBC), hepatocellular carcinoma and intrahepatic cholangiocarcinoma [19][20][21][22][23][24][25][26][31][32][33][34]. Within these reports there is evidence that higher MNX1-AS1 expression is correlated with detrimental pathological features and worse clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation

Wang

Yao

et al. 2022

J Exp Clin Cancer Res

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Background Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. Some glycolytic enzymes such as PKM2, the dominant pyruvate kinase in cancer cells, have been shown to engage in non-glycolytic functions that contribute to tumor metabolism. However, the precise mechanisms are not completely understood. Methods The role of MNX1-AS1 in hepatocellular carcinoma progression was assessed both in vitro and in vivo. Northern blotting, RNA pulldown, mass spectrometry, RNA-binding protein immunoprecipitation, ChIP, luciferase reporter assays, RNA FISH and immunofluorescence staining were used to explore the detail molecular mechanism of MNX1-AS1 in hepatocellular carcinoma (HCC). Results Here we dissect how MNX1-AS1, a long non-coding RNA (lncRNA), reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the cell nucleus. We found that MNX1-AS1 expression was frequently overexpressed in HCC-derived cell lines and tissues compared to their normal hepatic cell counterparts, a finding consistent with its status as pan-cancer expressed lncRNA. In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. In response to EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, GLUT1 and PDK1) are upregulated though the coactivator function of PKM2. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in xenograft models, indicative of the significant contribution of MNX1-AS1 to tumorigenic phenotypes. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. Conclusions Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.

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LncRNA MNX1-AS1 sustains inactivation of Hippo pathway through a positive feedback loop with USP16/IGF2BP3 axis in gallbladder cancer

Cited by 23 publications

References 47 publications

STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent

STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent

The Pleiotropic Ubiquitin-Specific Peptidase 16 and Its Many Substrates

MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation

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