LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2

Wang, Hongquan; Wang, Yan; Lai, Shihui; Zhao, Liang; Liu, Wenhui; Liu, Shiqian; Chen, Chien-Jen; Wang, Jinhua; Du, Guanhua; Tang, Bo

doi:10.1038/s41420-022-01234-8

Cited by 23 publications

(14 citation statements)

References 62 publications

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“…Conversely, no interaction was observed between SHIP2 and other notable E3 ligases, such as SIAH2, WWP2, MUL1, and Cul4A (Fig. 6 A) [ 28 ]. This underscores the specificity of the SHIP2-NEDD4 binding and suggests that the interaction between SHIP2 and its E3 ligase may occur in a tissue-specific manner.…”

Section: Resultsmentioning

confidence: 99%

PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer

Xu,

Xiang,

Yang

et al. 2024

J Exp Clin Cancer Res

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Background Prohibitin 2 (PHB2) exhibits opposite functions of promoting or inhibiting tumour across various cancer types. In this study, we aim to investigate its functions and underlying mechanisms in the context of gastric cancer (GC). Methods PHB2 protein expression levels in GC and normal tissues were examined using western blot and immunohistochemistry. PHB2 expression level associations with patient outcomes were examined through Kaplan–Meier plotter analysis utilizing GEO datasets (GSE14210 and GSE29272). The biological role of PHB2 and its subsequent regulatory mechanisms were elucidated in vitro and in vivo. GC cell viability and proliferation were assessed using MTT cell viability analysis, clonogenic assays, and BrdU incorporation assays, while the growth of GC xenografted tumours was measured via IHC staining of Ki67. The interaction among PHB2 and SHIP2, as well as between SHIP2 and NEDD4, was identified through co-immunoprecipitation, GST pull-down assays, and deletion-mapping experiments. SHIP2 ubiquitination and degradation were assessed using cycloheximide treatment, plasmid transfection and co-immunoprecipitation, followed by western blot analysis. Results Our analysis revealed a substantial increase in PHB2 expression in GC tissues compared to adjacent normal tissues. Notably, higher PHB2 levels correlated with poorer patient outcomes, suggesting its clinical relevance. Functionally, silencing PHB2 in GC cells significantly reduced cell proliferation and retarded GC tumour growth, whereas overexpression of PHB2 further enhanced GC cell proliferation. Mechanistically, PHB2 physically interacted with Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) in the cytoplasm of GC cells, thus leading to SHIP2 degradation via its novel E3 ligase NEDD4. It subsequently activated the PI3K/Akt signaling pathway and thus promoted GC cell proliferation. Conclusions Our findings highlight the importance of PHB2 upregulation in driving GC progression and its association with adverse patient outcomes. Understanding the functional impact of PHB2 on GC growth contributes valuable insights into the molecular underpinnings of GC and may pave the way for the development of targeted therapies to improve patient outcomes.

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Section: Resultsmentioning

confidence: 99%

PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer

Xu,

Xiang,

Yang

et al. 2024

J Exp Clin Cancer Res

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“…And ALKBH5-dependent demethylation drives lipogenesis and NAFLD-HCC progression via stabilizing LINC01468, which accelerates cullin4A (CUL4A)-linked degradation of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2). 308 Nevertheless, another study demonstrated that overexpressed ALKBH5 could ameliorate liver fibrosis and inactivate Hepatic stellate cells (HSCs) via upregulating Patched 1 (PTCH1). 309 Moreover, YTHDF3 was also reported to restrain liver fibrosis and HSC activation via facilitating peroxiredoxin 3 (PRDX3) translation in an m6A-dependent manner.…”

Section: Rna Modifications and Cellular Metabolismmentioning

confidence: 99%

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

Liu,

Zheng,

et al. 2024

Sig Transduct Target Ther

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Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2′-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.

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“…This ALKBH5-mediated lncRNA NEAT1 then acts as a sponge for miR-214, promoting the proliferation and migration of HCC cells. Moreover, m6A-modified LINC01468 is dependent on ALKBH5, which can enhance the stability of LINC01468 and upregulate its expression [ 93 ]. Upregulated LINC01468, in turn, interacts with SHIP2, enhancing CUL4A-associated degradation and enabling the activation of the PI3K/AKT/mTOR signaling pathway, thereby fueling lipogenesis and HCC progression.…”

Section: Biological Function Of Methylation Modification In Ncrnas In...mentioning

confidence: 99%

Non-coding RNA methylation modifications in hepatocellular carcinoma: interactions and potential implications

Shi,

Chu,

Zeng

et al. 2023

Cell Commun Signal

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RNA methylation modification plays a crucial role as an epigenetic regulator in the oncogenesis of hepatocellular carcinoma (HCC). Numerous studies have investigated the molecular mechanisms underlying the methylation of protein-coding RNAs in the progression of HCC. Beyond their impact on mRNA, methylation modifications also influence the biological functions of non-coding RNAs (ncRNAs). Here, we present an advanced and comprehensive overview of the interplay between methylation modifications and ncRNAs in HCC, with a specific focus on their potential implications for the tumor immune microenvironment. Moreover, we summarize promising therapeutic targets for HCC based on methylation-related proteins. In the future, a more profound investigation is warranted to elucidate the effects of ncRNA methylation modifications on HCC pathogenesis and devise valuable intervention strategies.

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LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2

Cited by 23 publications

References 62 publications

PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer

PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

Non-coding RNA methylation modifications in hepatocellular carcinoma: interactions and potential implications

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