SRC-3, a Steroid Receptor Coactivator: Implication in Cancer

Li, Licen; Deng, Chu‐Xia; Chen, Qiang

doi:10.3390/ijms22094760

Cited by 16 publications

(21 citation statements)

References 171 publications

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“…Interestingly, analysis of separate publically available RNA-seq dataset (GEO accession: GSE65099) ( 45 ) showed that SRC-3 RNA levels are significantly increased in the endometrium of patients diagnosed with RPL ( Figure 2F ), suggesting that perturbation of the homeostatic levels of SRC-3 may be linked to this endometrial pathology. It's important to note that dysregulation of SRC-3 expression is known as a critical causal factor in the genesis and progression of numerous tissue pathologies, including tumorigenesis and metastasis ( 14 , 46 , 47 ).…”

Section: Resultsmentioning

confidence: 99%

Decidualization of human endometrial stromal cells requires steroid receptor coactivator-3

Maurya

Szwarc

Lonard

et al. 2022

Front. Reprod. Health

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Steroid receptor coactivator-3 (SRC-3; also known as NCOA3 or AIB1) is a member of the multifunctional p160/SRC family of coactivators, which also includes SRC-1 and SRC-2. Clinical and cell-based studies as well as investigations on mice have demonstrated pivotal roles for each SRC in numerous physiological and pathophysiological contexts, underscoring their functional pleiotropy. We previously demonstrated the critical involvement of SRC-2 in murine embryo implantation as well as in human endometrial stromal cell (HESC) decidualization, a cellular transformation process required for trophoblast invasion and ultimately placentation. We show here that, like SRC-2, SRC-3 is expressed in the epithelial and stromal cellular compartments of the human endometrium during the proliferative and secretory phase of the menstrual cycle as well as in cultured HESCs. We also found that SRC-3 depletion in cultured HESCs results in a significant attenuation in the induction of a wide-range of established biomarkers of decidualization, despite exposure of these cells to a deciduogenic stimulus and normal progesterone receptor expression. These molecular findings are supported at the cellular level by the inability of HESCs to morphologically transform from a stromal fibroblastoid cell to an epithelioid decidual cell when endogenous SRC-3 levels are markedly reduced. To identify genes, signaling pathways and networks that are controlled by SRC-3 and potentially important for hormone-dependent decidualization, we performed RNA-sequencing on HESCs in which SRC-3 levels were significantly reduced at the time of administering the deciduogenic stimulus. Comparing HESC controls with HESCs deficient in SRC-3, gene enrichment analysis of the differentially expressed gene set revealed an overrepresentation of genes involved in chromatin remodeling, cell proliferation/motility, and programmed cell death. These predictive bioanalytic results were confirmed by the demonstration that SRC-3 is required for the expansion, migratory and invasive activities of the HESC population, cellular properties that are required in vivo in the formation or functioning of the decidua. Collectively, our results support SRC-3 as an important coregulator in HESC decidualization. Since perturbation of normal homeostatic levels of SRC-3 is linked with common gynecological disorders diagnosed in reproductive age women, this endometrial coregulator—along with its new molecular targets described here—may open novel clinical avenues in the diagnosis and/or treatment of a non-receptive endometrium, particularly in patients presenting non-aneuploid early pregnancy loss.

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Section: Resultsmentioning

confidence: 99%

Decidualization of human endometrial stromal cells requires steroid receptor coactivator-3

Maurya

Szwarc

Lonard

et al. 2022

Front. Reprod. Health

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“…EGFR is increasingly considered a biomarker of tumor drug resistance, and its amplification or secondary mutation occurs under the pressure of drugs ( Jang et al, 2020 ). SRC, a proto-oncogene complex protein kinase, promotes the development of cancer in many respects ( Li L. et al, 2021 ). SRC kinase plays an important role in promoting tumor growth and progression, and its activity is related to the low survival rate of patients ( Dasgupta et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Investigation into the in vivo mechanism of diosmetin in patients with breast cancer and COVID-19 using bioinformatics

Wang

Long

et al. 2022

Front. Pharmacol.

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Patients with breast cancer are prone to SARS-CoV-2 infection [the causative virus of coronavirus disease (COVID-19)] due to their lack of immunity. In the current study, we examined the mechanism of action of Diosmetin, a flavonoid with anti-inflammatory properties, in patients with BRCA infected with SARS-CoV-2.We used bioinformatics technology to analyze the binding ability, biological function, and other biological characteristics of Diosmetinin vivo and examine the core target and potential mechanism of action of Diosmetin in patients with patients with breast cancer infected with SARS-CoV-2. A prognostic model of SARS-COV-2–infected breast cancer patients was constructed, and the core genes were screened out, revealing the correlation between these core genes and clinicopathological characteristics, survival rate, and high-risk and low-risk populations. The docking results revealed that Diosmetin binds well to the core genes of patients with breast cancer with COVID-19. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that Diosmetin inhibited inflammation, enhanced immune function, and regulated the cellular microenvironment in patients with BRCA/COVID-19. For the first time, we reveal the molecular functions and potential targets of Diosmetin in patients with breast cancer infected with SARS-CoV-2, improving the reliability of the new drug and laying the foundation for further research and development.

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“…Our previous ndings has revealed that the histone methyltransferase NSD2 protects SRC-3 from degradation through forming liquid-liquid phase separation and renders resistance to PIs. 19 SRC-3 promotes numerous aspects of cancer, such as initiation, progression, and chemoresistance 25 , and suppression of SRC-3 levels and/or activity are e cient enough to alter its transcriptome. 26,27 Several studies have demonstrated that stimuli could induce multiple posttranslational modi cations of SRC-3, including phosphorylation, ubiquitination, SUMOylation, acetylation and methylation 25,28 .…”

Section: Discussionmentioning

confidence: 99%

“…19 SRC-3 promotes numerous aspects of cancer, such as initiation, progression, and chemoresistance 25 , and suppression of SRC-3 levels and/or activity are e cient enough to alter its transcriptome. 26,27 Several studies have demonstrated that stimuli could induce multiple posttranslational modi cations of SRC-3, including phosphorylation, ubiquitination, SUMOylation, acetylation and methylation 25,28 . In this study, we report that hypoxia is a new stimulates for SRC-3 expression without affect its transcription level.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma

Guo

Wang

et al. 2022

Oncogene

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The bone marrow microenvironment where multiple myeloma (MM) originated is hypoxic and an important stimulus for initiation of drug resistance to chemotherapies, but the underlying mechanisms and key regulators are still indistinct. In the current study, we found that hypoxia stimulus easily induced chemoresistance to proteasome inhibitors (PIs) but not to other chemicals, and the steroid receptor coactivator 3 (SRC-3) expression was remarkably augmented at posttranslational level. Protein interactome analysis identi ed SENP1 as a key modi er of SRC-3 stability, as deSUMOylation by SENP1 attenuated the K11-linked polyubiquitination of SRC-3. Depletion of SENP1 in MM cells by CRISPR/cas9 sgRNA, or in SENP1 / CD19 Cre/+ B cells, accelerated the degradation of SRC-3, and overcame the resistance to PIs at vast scale, which phenotype was similar to administration of SENP1inhibitor Momordin Ιc (Mc) in the Vk*Myc and 5TGM1 mouse models and patient derived xenograft (PDX) of myeloma. Importantly, SENP1 level was positively correlated with SRC-3 level in the tissues from refractory/relapsed MM, as well as in xenograft tissues from mice treated with bortezomib and Mc. Taken together, our ndings suggest that hypoxia induced SENP1 is a crucial regulator of chemoresistance to PIs, and shed light on developing therapeutic strategies to overcome chemoresistance by using small molecules targeting SENP1 or SRC-3.

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SRC-3, a Steroid Receptor Coactivator: Implication in Cancer

Cited by 16 publications

References 171 publications

Decidualization of human endometrial stromal cells requires steroid receptor coactivator-3

Decidualization of human endometrial stromal cells requires steroid receptor coactivator-3

Investigation into the in vivo mechanism of diosmetin in patients with breast cancer and COVID-19 using bioinformatics

Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma

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