Endometrial cancer (EC) derived G3BP1 overexpression and mutant promote EC tumorigenesis and metastasis via SPOP/ERα axis.

BACKGROUND: Ras-GTPase-activating protein binding protein 1 (G3BP1) is an oncogenic factor, which highly expressed in a variety of cancers. In recent years, G3BP1 has been reported to promote the development of prostate cancer by inhibiting the degradation of AR through inhibiting SPOP. However, whether G3BP1 contributes in a similar manner to the abnormal accumulation of ERα, which is also an important target for hormone therapy, remains unknown. This article addresses this issue and explores potential mechanisms. METHODS: Bioinformatics tools were used for G3BP1 expression analysis, survival analysis, and clinical association analysis. Immunohistochemical staining was used to examine the correlation between G3BP1 and ERα in EC patients. In addition, western blot and co-immunoprecipitation were used to detect the half-life of G3BP1 and mutant, and the effect of G3BP1 and mutant on the ubiquitination and degradation of ERα mediated by SPOP. Then, the oncogenic functions of G3BP1 dependent on the SPOP/ERα axis were determined by CCK8 cell proliferation assay, colony formation assay and cell migration assay. Finally, we established the EC cells treated or untreated with fulvestrant, exploring the possibility of fulvestrant combined with the reduction of G3BP1 to improve the efficacy of fulvestrant. RESULTS: G3BP1 is abnormally high expressed and characterized by high-frequency mutation in EC. In addition, there is a positive correlation between G3BP1 protein and ERα protein. Mechanistically, both G3BP1 and mutant, the latter is displaying the longer half-life, competitively bind SPOP with ERα, thereby inhibiting SPOP-mediated ubiquitination and degradation of ERα. Functionally, G3BP1 and mutant promote the proliferation and migration of EC cells by regulating the G3BP1/SPOP/ERα axis. However, fulvestrant can reverse the cancer-promoting effects of G3BP1 and mutant. CONCLUSIONS: G3BP1 and its mutant positively regulate ERα signaling pathway by inhibiting SPOP-mediated ubiquitination and degradation of ERα, indicating the promising effect of fulvestrant on the suppression the occurrence and development of EC with high expressed G3BP1 and G3BP1 mutants. Video Abstract.

The crosstalk between ubiquitination and endocrine therapy.

Endocrine therapy (ET), also known as hormone therapy, refers to the treatment of tumors by regulating and changing the endocrine environment and hormone levels. Its related mechanism is mainly through reducing hormone levels and blocking the binding of hormones to corresponding receptors, thus blocking the signal transduction pathway to stimulate tumor growth. However, with the application of ET, some patients show resistance to ET, which is attributed to abnormal accumulation of hormone receptors (HRs) and the production of multiple mutants of HRs. The targeted degradation of abnormal accumulation protein mediated by ubiquitination is an important approach that regulates the protein level and function of intracellular proteins in eukaryotes. Here, we provide a brief description of the traditional and novel drugs available for ET in this review. Then, we introduce the link between ubiquitination and ET. In the end, we elaborate the clinical application of ET combined with ubiquitination-related molecules. KEY MESSAGES: • A brief description of the traditional and novel drugs available for endocrine therapy (ET). • The link between ubiquitination and ET. • The clinical application of ET combined with ubiquitination-related molecules.

Roles of estrogen receptor α in endometrial carcinoma (Review).

Endometrial carcinoma (EC) is a group of endometrial epithelial malignancies, most of which are adenocarcinomas and occur in perimenopausal and postmenopausal women. It is one of the most common carcinomas of the female reproductive system. It has been shown that the occurrence and development of EC is closely associated with the interaction between estrogen (estradiol, E2) and estrogen receptors (ERs), particularly ERα. As a key nuclear transcription factor, ERα is a carcinogenic factor in EC. Its interactions with upstream and downstream effectors and co-regulators have important implications for the proliferation, metastasis, invasion and inhibition of apoptosis of EC. In the present review, the structure of ERα and the regulation of ERα in multiple dimensions are described. In addition, the classical E2/ERα signaling pathway and the crosstalk between ERα and other EC regulators are elucidated, as well as the therapeutic targeting of ERα, which may provide a new direction for clinical applications of ERα in the future.

Siah1 in cancer and nervous system diseases (Review).

The dysregulation of the ubiquitin­proteasome system will result in the abnormal accumulation and dysfunction of proteins, thus leading to severe diseases. Seven in absentia homolog 1 (Siah1), an E3 ubiquitin ligase, has attracted wide attention due to its varied functions in physiological and pathological conditions, and the numerous newly discovered Siah1 substrates. In cancer and nervous system diseases, the functions of Siah1 as a promoter or a suppressor of diseases are related to the change in cellular microenvironment and subcellular localization. At the same time, complex upstream regulations make Siah1 different from other E3 ubiquitin ligases. Understanding the molecular mechanism of Siah1 will help the study of various signaling pathways and benefit the therapeutic strategy of human diseases (e.g., cancer and nervous system diseases). In the present review, the functions and regulations of Siah1 are described. Moreover, novel substrates of Siah1 discovered in recent studies will be highlighted in cancer and nervous system diseases, providing ideas for future research and clinical targeted therapies using Siah1.

The roles of G3BP1 in human diseases (review).

Ras-GTPase-activating protein binding protein 1 (G3BP1) is a multifunctional binding protein involved in a variety of biological functions, including cell proliferation, metastasis, apoptosis, differentiation and RNA metabolism. It has been revealed that G3BP1, as an antiviral factor, can interact with viral proteins and regulate the assembly of stress granules (SGs), which can inhibit viral replication. Furthermore, several viruses have the ability to hijack G3BP1 as a cofactor, recruiting translation initiation factors to promote viral proliferation. However, many functions of G3BP1 are associated with other diseases. In various cancers, G3BP1 is a cancer-promoting factor, which can promote the proliferation, invasion and metastasis of cancer cells. Moreover, compared with normal tissues, G3BP1 expression is higher in tumor tissues, indicating that it can be used as an indicator for cancer diagnosis. In this review, the structure of G3BP1 and the regulation of G3BP1 in multiple dimensions are described. In addition, the effects and potential mechanisms of G3BP1 on various carcinomas, viral infections, nervous system diseases and cardiovascular diseases are elucidated, which may provide a direction for clinical applications of G3BP1 in the future.

Fate of hematopoietic stem cells determined by Notch1 signaling (Review).

Regulation of the fate of hematopoietic stem cells (HSCs), including silencing, self-renewal or differentiation into blood line cells, is crucial to maintain the homeostasis of the human blood system and prevent leukemia. Notch1, a key receptor in the Notch signaling pathway, plays an important regulatory role in these properties of HSCs, particularly in the maintenance of the stemness of HSCs. In recent decades, the ubiquitination modification of Notch1 has been gradually revealed, and also demonstrated to affect the proliferation and differentiation of HSCs. Therefore, a detailed elucidation of Notch1 and its ubiquitination modification may help to improve understanding of the maintenance of HSC properties and the pathogenesis of leukemia. In addition, it may aid in identifying potential therapeutic targets for specific leukemias and provide potential prognostic indicators for HSC transplantation (HSCT). In the present review, the association between Notch1 and HSCs and the link between the ubiquitination modification of Notch1 and HSCs were described. In addition, the association between abnormal HSCs mediated by Notch1 or ubiquitinated Notch1and T-cell acute lymphoblastic leukemia (T-ALL) was also examined, which provides a promising direction for clinical application.

Variation of Critical Water Pressure for Hydraulic Fracturing in Cement Mortar under Sulfate Attack.

Hydraulic fracturing may be induced easily in a cement-based structure in a sulfate-rich environment, which threatens engineering safety. In order to investigate the evolution of critical water pressure, a series of hydraulic fracturing tests and splitting tensile strength tests on the cement mortar under different sulfate-exposure periods are performed. The critical water pressure of the cement mortar under sulfate attack experiences an initial increase stage and a subsequent decrease stage. A stress intensity factor is modified by two proposed damage variables which are crack length and fracture stress. Then, the relationship between the critical water pressure and the tensile strength is established. Moreover, an evolution model of the critical water pressure is proposed, which reveals that the matrix tensile strength and porosity of cement mortar strongly affect the critical water pressure evolution. Additionally, an empirical formula is suggested to describe the critical water pressure evolution of the cement mortar under sulfate attack, and its validity is verified by experimental results.