Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5

Liang, Shiwei; Zhu, Chuxu; Suo, Caixia; Wei, Haoran; Yu, Yingxuan; Gu, Xuemei; Chen, Liang; Yuan, Mengqiu; Shen, Shengqi; Li, Shiting; Sun, Linchong; Gao, Ping

doi:10.3389/fonc.2022.857968

Cited by 15 publications

(14 citation statements)

References 45 publications

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“…This indicates that our results are reproducible and reliable to some extent. A recent study validated PGAM5 function, thereby providing sufficient evidence to support the reliability and reproducibility of our results [ 68 ]. In summary, our study not only has a novelty but also provides further support for previous research.…”

Section: Discussionsupporting

confidence: 73%

A Mitophagy-Related Gene Signature for Subtype Identification and Prognosis Prediction of Hepatocellular Carcinoma

Liu

Wang

et al. 2022

IJMS

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Globally, hepatocellular carcinoma (HCC) is the sixth most common cancer. In this study, the correlation between mitophagy and HCC prognosis was evaluated using data from The Cancer Genome Atlas (TCGA). Clinical and transcriptomic data of HCC patients were downloaded from TCGA dataset, and mitophagy-related gene (MRG) datasets were obtained from the Molecular Signature Database. Then, a consensus clustering analysis was performed to classify the patients into two clusters. Furthermore, tumor prognosis, clinicopathological features, functional analysis, immune infiltration, immune checkpoint (IC)-related gene expression level, tumor stem cells, ferroptosis status, and N6-methyladenosine analysis were compared between the two clusters. Finally, a mitophagy-related signature was developed. Two clusters (C1 and C2) were identified using the consensus clustering analysis based on the MRG signature. Patients with the C1 subtype exhibited upregulated pathways with better liver function, downregulated cancer-related pathways, lower cancer stem cell scores, lower Tumor Immune Dysfunction and Exclusion scores (TIDE), different ferroptosis status, and better prognosis compared with the patients with the C2 subtype. The C2 subtype was characterized by the increased grade of HCC, as well as the increased number of immune-related pathways and m6A-related genes. Higher immune scores were also observed for the C2 subtype. A signature containing four MRGs (PGAM5, SQSTM1, ATG9A, and GABARAPL1) which can accurately predict the prognosis of HCC patients was then identified. This four-gene signature exhibited a predictive effect in five other cancer types, namely glioma, uveal melanoma, acute myeloid leukemia, adrenocortical carcinoma, and mesothelioma. The mitophagy-associated subtypes of HCC were closely related to the immune microenvironment, immune checkpoint-related gene expression, cancer stem cells, ferroptosis status, m6A, prognosis, and HCC progression. The established MRG signature could predict prognosis in patients with HCC.

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Section: Discussionsupporting

confidence: 73%

A Mitophagy-Related Gene Signature for Subtype Identification and Prognosis Prediction of Hepatocellular Carcinoma

Liu

Wang

et al. 2022

IJMS

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“…Therefore, the above data suggest that mitophagy, mediated by PINK1 and NIPSNAP1, plays a crutial role in liver fibrosis. However, the mitophagy has a context‐dependent impact in different liver diseases (Li et al, 2020; Liang et al, 2022). On one hand, mitophagy supports hepatic fibrogenesis (Dou et al, 2021; Kang et al, 2016), while mitophagy limits liver fibrosis (Qiu et al, 2019; Wu et al, 2020) on the other hand.…”

Section: Discussionmentioning

confidence: 99%

SIRT3 regulates mitophagy in liver fibrosis through deacetylation of PINK1/NIPSNAP1

Wang

et al. 2023

Journal Cellular Physiology

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Damaged mitochondria, a key factor in liver fibrosis, can be removed by the mitophagy pathway to maintain homeostasis of the intracellular environment to alleviate the development of fibrosis. PINK1 (PTEN‐induced kinase 1) and NIPSNAP1 (nonneuronal SNAP25‐like protein 1), which cooperatively regulate mitophagy, have been predicted to include the sites of lysine acetylation related to SIRT3 (mitochondrial deacetylase sirtuin 3). Our study aimed to discuss whether SIRT3 deacetylates PINK1 and NIPSNAP1 to regulate mitophagy in liver fibrosis. Carbon tetrachloride (CCl4)‐induced liver fibrosis as an in vivo model and LX‐2 cells as activated cells were used to simulate liver fibrosis. SIRT3 expression was significantly decreased in mice in response to CCl4, and SIRT3 knockout in vivo significantly deepened the severity of liver fibrosis, as indicated by increased α‐SMA and Col1a1 levels both in vivo and in vitro. SIRT3 overexpression decreased α‐SMA and Col1a1 levels. Furthermore, SIRT3 significantly regulated mitophagy in liver fibrosis, as demonstrated by LC3‐Ⅱ/Ⅰ and p62 expression and colocalization between TOM20 and LAMP1. Importantly, PINK1 and NIPSNAP1 expression was also decreased in liver fibrosis, and PINK1 and NIPSNAP1 overexpression significantly improved mitophagy and attenuated ECM production. Furthermore, after simultaneously interfering with PINK1 or NIPSNAP1 and overexpressing SIRT3, the effect of SIRT3 on improving mitophagy and alleviating liver fibrosis was disrupted. Mechanistically, we show that SIRT3, as a mitochondrial deacetylase, specifically regulates the acetylation of PINK1 and NIPSNAP1 to mediate the mitophagy pathway in liver fibrosis. SIRT3‐mediated PINK1 and NIPSNAP1 deacetylation is a novel molecular mechanism in liver fibrosis.

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“…For example, in response to combined treatments of the mitochondrial uncoupler of oxidative phosphorylation and glucose deprivation, SND1 was imported into mitochondria and activated dynamin-related protein 1 (DRP1)-mediated mitophagy to promote HCC cell proliferation and tumor growth both in vitro and in vivo. 10 SND1 was also reported to enhance cholesterol synthesis and deregulate cholesterol homeostasis in hepatoma cells. 14 In current study, we reported a novel role of SND1 in regulating aerobic glycolysis in liver cancer cells, which contributes to liver cancer cell malignancies and sorafenib resistance.…”

Section: Discussionmentioning

confidence: 99%

“…A couple of studies indicated SND1 had effects on material and energy metabolism of HCC cells. For example, in response to combined treatments of the mitochondrial uncoupler of oxidative phosphorylation and glucose deprivation, SND1 was imported into mitochondria and activated dynamin‐related protein 1 (DRP1)‐mediated mitophagy to promote HCC cell proliferation and tumor growth both in vitro and in vivo 10 . SND1 was also reported to enhance cholesterol synthesis and deregulate cholesterol homeostasis in hepatoma cells 14 .…”

Section: Discussionmentioning

confidence: 99%

SNHG1, interacting with SND1, contributes to sorafenib resistance of liver cancer cells by increasing m6A‐mediated SLC7A11 expression and promoting aerobic glycolysis

Li,

Shen

et al. 2023

Environmental Toxicology

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Aerobic glycolysis plays an important role in multidrug resistance of cancer cells. Here, we screened different expressed lncRNAs associated with sorafenib resistance of liver cancer cells, by intersecting the bioinformatics analyses of TCGA and GEO (the GSE62813 dataset) databases. Our results revealed that the 18 upregulated lncRNAs in the intersection are associated with and enriched in metabolism of small molecule organic acids, suggesting their potential in glycolysis. The lncRNA small nucleolar RNA host gene 1 (Snhg1) was chosen as a potential regulator of aerobic glycolysis in liver cancer cells, for its significant promotion on lactate production. Gain‐ and loss‐of‐function experiments mediated by Crispr‐Cas9 technique in HepG2 cells indicated that Snhg1 promoted cell proliferation, invasion, sorafenib resistance, and aerobic glycolysis. In the mechanism exploration, we found that Snhg1 can interact with SND1 protein, a famous RNA binding protein and recently identified “Reader” of N6‐methyladenosine (m6A). SND1 was demonstrated to be positively regulated by Snhg1 and had similar promoting effects on proliferation, invasion, sorafenib resistance, and aerobic glycolysis of HepG2 cells. SND1 bound with and promoted the expression of SLC7A11, an aerobic glycolysis regulator. Furthermore, either silencing SLC7A11 or blocking aerobic glycolysis with 2‐deoxy‐d‐glucose (2‐DG) was able to reverse the promotion of Snhg1 overexpression on malignancy, sorafenib resistance, and aerobic glycolysis of HepG2 cells. Finally, in a liver cancer xenograft mouse model, we found that formed tumors with Snhg1‐knocked‐down HepG2 cells were more sensitive to sorafenib administration. Altogether, SNHG1 contributes to sorafenib resistance of liver cancer cells by promoting SND1‐m6A‐SLC7A11‐mediated aerobic glycolysis.

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Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5

Cited by 15 publications

References 45 publications

A Mitophagy-Related Gene Signature for Subtype Identification and Prognosis Prediction of Hepatocellular Carcinoma

A Mitophagy-Related Gene Signature for Subtype Identification and Prognosis Prediction of Hepatocellular Carcinoma

SIRT3 regulates mitophagy in liver fibrosis through deacetylation of PINK1/NIPSNAP1

SNHG1, interacting with SND1, contributes to sorafenib resistance of liver cancer cells by increasing m6A‐mediated SLC7A11 expression and promoting aerobic glycolysis

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