The role of Siah2 in tumorigenesis and cancer therapy

Li, Kailang; Li, Jinyun; Ye, Meng; Jin, Xiaofeng

doi:10.1016/j.gene.2021.146028

Cited by 17 publications

(16 citation statements)

References 113 publications

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“…PTMs (e.g., glycosylation, phosphorylation, ubiquitination, palmitoylation, SUMOylation, and acetylation) have been demonstrated to play an essential role in the modulation of protein stabilization and protein-protein interactions of the PD-1/PD-L1 axis (30)(31)(32). Siah2 is known to play an important role in tumorigenesis and cancer progression (18). Numerous studies have determined that Siah2 promotes tumorigenesis in a variety of human malignancies (18).…”

Section: Discussionmentioning

confidence: 99%

“…Siah2 is known to play an important role in tumorigenesis and cancer progression (18). Numerous studies have determined that Siah2 promotes tumorigenesis in a variety of human malignancies (18). However, several studies revealed that Siah2 exhibited tumor suppressor function by promoting the proteasomemediated degradation of several oncoproteins, suggesting that Siah2 could exert its biological function depending on different stages of tumor development (18).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have determined that Siah2 promotes tumorigenesis in a variety of human malignancies (18). However, several studies revealed that Siah2 exhibited tumor suppressor function by promoting the proteasomemediated degradation of several oncoproteins, suggesting that Siah2 could exert its biological function depending on different stages of tumor development (18). Moreover, Siah2 is subject to complex regulation, especially the phosphorylation of Siah2 by a variety of protein kinases to regulate its stability and activity (18).…”

Section: Discussionmentioning

confidence: 99%

“…However, several studies revealed that Siah2 exhibited tumor suppressor function by promoting the proteasomemediated degradation of several oncoproteins, suggesting that Siah2 could exert its biological function depending on different stages of tumor development (18). Moreover, Siah2 is subject to complex regulation, especially the phosphorylation of Siah2 by a variety of protein kinases to regulate its stability and activity (18). However, the role of Siah2 in regulating tumor immunoenvironment in CCA, and the underlying molecular mechanism of this potential Siah2-regulated PD-L1 protein level has not been yet elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…SIAH1 and Siah2 are highly homologous RING domain E3 ligases that often target common proteins for degradation (17). Two SIAH homologs in humans (SIAH1 and Siah2) and three homologs in mice (Siah1a, Siah1b, and Siah2) have been reported (18). SIAH proteins contain an N-terminal RING domain and a C-terminal substrate-binding domain (SBD) (19), which are involved in ubiquitination of diverse substrates and other biological processes such as RAS signaling, DNA damage, hypoxia, p38/JNK/NF-кB pathways, and transcription (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

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Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

Zheng

Wang

et al. 2022

Front. Immunol.

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N6-methyladenosine (m6A) has been reported as an important mechanism of post-transcriptional regulation. Programmed death ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. In addition, seven in absentia homolog 2 (Siah2), a RING E3 ubiquitin ligase, has been involved in tumorigenesis and cancer progression. However, the role of m6A-METTL14-Siah2-PD-L1 axis in immunotherapy remains to be elucidated. In this study, we showed that METTL14, a component of the m6A methyltransferase complex, induced Siah2 expression in cholangiocarcinoma (CCA). METTL14 was shown to enrich m6A modifications in the 3’UTR region of the Siah2 mRNA, thereby promoting its degradation in an YTHDF2-dependent manner. Furthermore, co-immunoprecipitation experiments demonstrated that Siah2 interacted with PD-L1 by promoting its K63-linked ubiquitination. We also observed that in vitro and in vivo Siah2 knockdown inhibited T cells expansion and cytotoxicity by sustaining tumor cell PD-L1 expression. The METTL14-Siah2-PD-L1–regulating axis was further confirmed in human CCA specimens. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with low Siah2 levels were more sensitive to anti-PD1 immunotherapy. Taken together, our results evidenced a new regulatory mechanism of Siah2 by METTL14-induced mRNA epigenetic modification and the potential role of Siah2 in cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

Zheng

Wang

et al. 2022

Front. Immunol.

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SIAH3 is frequently epigenetically silenced in cancer and regulates mitochondrial metabolism

Deutschmeyer,

Schlaudraff,

Walesch

et al. 2024

Intl Journal of Cancer

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Of the seven in absentia homologue (SIAH) family, three members have been identified in the human genome. In contrast to the E3 ubiquitin ligase encoding SIAH1 and SIAH2, little is known on the regulation and function of SIAH3 in tumorigenesis. In this study, we reveal that SIAH3 is frequently epigenetically silenced in different cancer entities, including cutaneous melanoma, lung adenocarcinoma and head and neck cancer. Low SIAH3 levels correlate with an impaired survival of cancer patients. Additionally, induced expression of SIAH3 reduces cell proliferation and induces cell death. Functionally, SIAH3 negatively affects cellular metabolism by shifting cells form aerobic oxidative phosphorylation to glycolysis. SIAH3 is localized in the mitochondrion and interacts with proteins involved in mitochondrial ribosome biogenesis and translation. We also report that SIAH3 interacts with ubiquitin ligases, including SIAH1 or SIAH2, and is degraded by them. These results suggest that SIAH3 acts as an epigenetically controlled tumor suppressor by regulating cellular metabolism through the inhibition of oxidative phosphorylation.

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Role of the ubiquitin–proteasome system on macrophages in the tumor microenvironment

Xiao,

Liu,

et al. 2024

Journal Cellular Physiology

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Tumor‐associated macrophages (TAMs) are key components of the tumor microenvironment, and their different polarization states play multiple roles in tumors by secreting cytokines, chemokines, and so on, which are closely related to tumor development. In addition, the enrichment of TAMs is often associated with poor prognosis of tumors. Thus, targeting TAMs is a potential tumor treatment strategy, in which therapeutic approaches such as reducing TAMs numbers, remodeling TAMs phenotypes, and altering their functions are being extensively investigated. Meanwhile, the ubiquitin–proteasome system (UPS), an important mechanism of protein hydrolysis in eukaryotic cells, participates in cellular processes by regulating the activity and stability of key proteins. Interestingly, UPS plays a dual role in the process of tumor development, and its role in TAMs deserve to be investigated in depth. This review builds on this foundation to further explore the multiple roles of UPS on TAMs and identifies a promising approach to treat tumors by targeting TAMs with UPS.

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The role of Siah2 in tumorigenesis and cancer therapy

Cited by 17 publications

References 113 publications

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

SIAH3 is frequently epigenetically silenced in cancer and regulates mitochondrial metabolism

Role of the ubiquitin–proteasome system on macrophages in the tumor microenvironment

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