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To date, >650 E3 ubiquitin ligases have been described in humans, including >600 really interesting new genes (RINGs), 28 homologous to E6-associated protein C-terminus (HECTs) and several RING-in-between-RINGs. They are considered key regulators and therapeutic targets of many types of human cancers, including gastric cancer (GC). Among them, some RING and HECT E3 ligases are closely related to the proliferation, infiltration and prognosis of GC. During the past few years, abnormal expressions and functions of many E3 ligases have been identified in GC. However, the functional roles of E3 ligases in GC have not been fully elucidated. The present article focuses on the functional roles of E3 ligases related to the proteasome in GC. In this comprehensive review, the latest research progress on E3 ligases involved in GC and elaborate their structure, classification, functional roles and therapeutic value in GC was summarized. Finally, 30 E3 ligases that serve essential roles in regulating the development of GC were described. Some of these ligases may serve as oncogenes or tumor suppressors in GC, whereas the pathological mechanism of others needs further study; for example, constitutive photomorphogenic 1. In conclusion, the present review demonstrated that E3 ligases are crucial tumor regulatory factors and potential therapeutic targets in GC. Therefore, more studies should focus on the therapeutic targeting of E3 ligases in GC.

Several recent studies suggested that TLKs are related to tumor progression. However, the function and action mechanism of TLK2 in GC remain elusive. We observed that TLK2 was signi cantly upregulated in GC and acted as an independent prognostic factor in GC patients. In line with these results, TLK2 silencing markedly reduced GC aggressiveness, whereas its overexpression had the opposite effect. IP-MS suggested that the effect of TLK2 expression on GC was mainly associated with metabolism reprogramming. TLK2 knockdown suppressed amino synthesis through downregulating the mTORC1 pathway and ASNS expression in GC. Mechanistically, mTORC1 directly interacted with ASNS and inhibited its protein degradation. Further experiments con rmed that ASNS protein degradation was ubiquitination degradation rather than degradation through autophagy. Inhibiting and activating the mTORC1 pathway can upregulate and downregulate ASNS ubiquitination, respectively. Moreover, the mTORC1 pathway can reverse the protein regulation of ASNS by TLK2. Notably, TLK2 regulated the ASNS mRNA levels. Further evidence con rmed that TLK2 directly interacted with ATF4, a transcription factor of ASNS, and promoted the expression of ATF4. Finally, we found kinase inhibitor Fostamatinib can signi cantly inhibit the proliferation, invasion, and migration of GC cells by inhibiting TLK2 enzyme activity. Taken together, this study reveals a novel functional link between TLK2, the mTORC1/ASNS axis, and GC. Therefore, TLK2 could be a potential therapeutic approach for GC target therapy.

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