L3MBTL2-mediated CGA transcriptional suppression promotes pancreatic cancer progression through modulating autophagy

Huang, Hua; Pan, Ruining; Zhao, Yue; Li, Huan; Zhu, Huiyu; Wang, Sijia; Khan, Aamir Ali; Wang, Juan; Liu, Xinhui

doi:10.1016/j.isci.2022.104249

Cited by 6 publications

(3 citation statements)

References 50 publications

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“…These observations confirmed that TP53INP2-modulated autophagy was essential for the survival of NPM1 -mutated leukemia cells. In keeping with our findings, TP53INP2 is reported to induce autophagy activation to promote pancreatic cancer progression [ 49 ]. Additionally, Hu et al claimed that TP53INP2-mediated basal autophagy makes liposarcoma cells more resistant to bortezomib-induced growth suppression [ 50 ].…”

Section: Discussionsupporting

confidence: 91%

Cytoplasmic Expression of TP53INP2 Modulated by Demethylase FTO and Mutant NPM1 Promotes Autophagy in Leukemia Cells

Huang

Sun

Tao

et al. 2023

IJMS

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Acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM1) mutation is a unique subtype of adult leukemia. Recent studies show that NPM1-mutated AML has high autophagy activity. However, the mechanism for upholding the high autophagic level is still not fully elucidated. In this study, we first identified that tumor protein p53 inducible nuclear protein 2 (TP53INP2) was highly expressed and cytoplasmically localized in NPM1-mutated AML cells. Subsequent data showed that the expression of TP53INP2 was upregulated by fat mass and obesity-associated protein (FTO)-mediated m6A modification. Meanwhile, TP53INP2 was delocalized to the cytoplasm by interacting with NPM1 mutants. Functionally, cytoplasmic TP53INP2 enhanced autophagy activity by promoting the interaction of microtubule-associated protein 1 light chain 3 (LC3) - autophagy-related 7 (ATG7) and further facilitated the survival of leukemia cells. Taken together, our study indicates that TP53INP2 plays an oncogenic role in maintaining the high autophagy activity of NPM1-mutated AML and provides further insight into autophagy-targeted therapy of this leukemia subtype.

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Section: Discussionsupporting

confidence: 91%

Cytoplasmic Expression of TP53INP2 Modulated by Demethylase FTO and Mutant NPM1 Promotes Autophagy in Leukemia Cells

Huang

Sun

Tao

et al. 2023

IJMS

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“…Huang et al. ( 54 ) have recently reported that L3MBTL2 promotes pancreatic cancer progression through transcriptional suppression of CGA ( 54 ). However, we found that CGA was undetectable in most osteosarcoma cell lines and tumor tissues in our previously published osteosarcoma RNA-seq data ( 33 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma

Zhong,

Wang,

Chen

et al. 2023

Sci. Adv.

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Osteosarcoma is a highly aggressive cancer and lacks effective therapeutic targets. We found that L3MBTL2 acts as a tumor suppressor by transcriptionally repressing IFIT2 in osteosarcoma. L3MBTL2 recruits the components of Polycomb repressive complex 1.6 to form condensates via both Pho-binding pockets and polybasic regions within carboxyl-terminal intrinsically disordered regions; the L3MBTL2-induced condensates are required for its tumor suppression. Multi-monoubiquitination of L3MBTL2 by UBE2O results in its proteasomal degradation, and the UBE2O/L3MBTL2 axis was crucial for osteosarcoma growth. There is a reverse correlation between L3MBTL2 and UBE2O in osteosarcoma tissues, and higher UBE2O and lower L3MBTL2 are associated with poorer prognosis in osteosarcoma. Pharmacological blockage of UBE2O by arsenic trioxide can enhance L3MBTL2-induced condensates and consequently suppress osteosarcoma growth. Our findings unveil a crucial biological function of L3MBTL2-induced condensates in mediating tumor suppression, proposing the UBE2O-L3MBTL2 axis as a potential cancer therapeutic target in osteosarcoma.

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“…Several proteins associated with PCGF6 like L3MBTL histone methyl-lysine binding protein 2 (L3MBTL2), E2F transcription factor 6 (E2F6) and MAX gene-associated protein (MGA) are common subunits of ncPRC1.6. Generally, these proteins act collaboratively to facilitate the loading of ncPRC1.6 to its target sites ( Huang et al, 2018 ; 2022 ; Dahlet et al, 2021 ).…”

Section: The Composition Of Pcg Complexesmentioning

confidence: 99%

Research advances of polycomb group proteins in regulating mammalian development

Li,

Mo,

Chen

et al. 2024

Front. Cell Dev. Biol.

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Polycomb group (PcG) proteins are a subset of epigenetic factors that are highly conserved throughout evolution. In mammals, PcG proteins can be classified into two muti-proteins complexes: Polycomb repressive complex 1 (PRC1) and PRC2. Increasing evidence has demonstrated that PcG complexes play critical roles in the regulation of gene expression, genomic imprinting, chromosome X-inactivation, and chromatin structure. Accordingly, the dysfunction of PcG proteins is tightly orchestrated with abnormal developmental processes. Here, we summarized and discussed the current knowledge of the biochemical and molecular functions of PcG complexes, especially the PRC1 and PRC2 in mammalian development including embryonic development and tissue development, which will shed further light on the deep understanding of the basic knowledge of PcGs and their functions for reproductive health and developmental disorders.

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L3MBTL2-mediated CGA transcriptional suppression promotes pancreatic cancer progression through modulating autophagy

Cited by 6 publications

References 50 publications

Cytoplasmic Expression of TP53INP2 Modulated by Demethylase FTO and Mutant NPM1 Promotes Autophagy in Leukemia Cells

Cytoplasmic Expression of TP53INP2 Modulated by Demethylase FTO and Mutant NPM1 Promotes Autophagy in Leukemia Cells

Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma

Research advances of polycomb group proteins in regulating mammalian development

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