Cancer metastasis, a process that primary tumor cells disseminate to secondary organs, is the most lethal and least effectively treated characteristic of human cancers. Kisspeptins are proteins encoded by the KISS1 ge...Cancer metastasis, a process that primary tumor cells disseminate to secondary organs, is the most lethal and least effectively treated characteristic of human cancers. Kisspeptins are proteins encoded by the KISS1 gene that was originally described as a melanoma metastasis suppressor gene. Then, Kisspeptins were discovered as the natural ligands of the G-protein-coupled receptor 54(GPR54) that is also called KISS1R. The KISS1/KISS1R signaling is essential to control Gn RH secretion during puberty and to establish mammalian reproductive function through the hypothalamic-pituitary-gonadal(HPG) axis. Although KISS1primarily plays a suppressive role in the metastasis progression in several cancer types, emerging evidence indicates that the physiological effect of KISS1/KISS1R in cancer metastasis is tissue context-dependent and still controversial. Here, we will discuss the epigenetic mechanism involved in the regulation of KISS1 gene expression, the context-dependent role of KISS1/KISS1R, prometastasis/anti-metastasis signaling pathways of KISS1/KISS1R, and the perspective anticancer therapeutics via targeting KISS1/KISS1R.展开更多
Ubiquitination plays critical roles in regulating various physiological events,such as protein degradation,activation,secretion,sorting and trafficking(Dang et al.,2021).The ubiquitination process involves three major...Ubiquitination plays critical roles in regulating various physiological events,such as protein degradation,activation,secretion,sorting and trafficking(Dang et al.,2021).The ubiquitination process involves three major steps,catalyzed by ubiquitin-activating enzymes(E1s),ubiquitin-conjugating enzymes(E2s),and ubiquitin ligases(E3s),respectively(Scheffner et al.,1995).展开更多
Much akin to ubiquitylation,neddylation is catalyzed by a cascade of three enzymes:E1 NEDD8-activating enzyme,E2 NEDD8-conjugating enzyme(UBE2M or UBE2F),and E3 NEDD8 ligases.The best-known neddylation substrates are ...Much akin to ubiquitylation,neddylation is catalyzed by a cascade of three enzymes:E1 NEDD8-activating enzyme,E2 NEDD8-conjugating enzyme(UBE2M or UBE2F),and E3 NEDD8 ligases.The best-known neddylation substrates are the members of cullin family,leading to the activation of Cullin-RING ligases,which regulate a variety of downstream biological processes largely via promoting ubiquitylation and subsequent proteasomal degradation of many key signaling proteins.Notably,neddylation enzymes and components of the Cullin-RING ligases are frequently altered in many human cancers and have been validated as promising cancer targets.As such,drug discovery efforts are underway to target neddylation-Cullin-RING ligases with a few selective small molecule inhibitors being advanced into various phases of clinical trials.This review firstly provides a brief introduction to neddylation,then focuses on lung cancer,and summarizes a wealth of current data showing how neddylation-Cullin-RING ligases are altered and affect the growth and survival of lung cancer cells,lung tumorigenesis,lung tumor microenvironment,and inflammatory response.A few reported small molecule inhibitors of neddylation enzymes as well as their activity against lung cancer cells are also summarized,and future perspectives with an ultimate goal of discovering effective treatment of lung cancer via targeting neddylation-Cullin-RING ligases are proposed.展开更多
Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmem- bran...Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmem- brane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled （FZD） receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin f-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiqui- tinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phos- phorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regu- lation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3.展开更多
文摘Cancer metastasis, a process that primary tumor cells disseminate to secondary organs, is the most lethal and least effectively treated characteristic of human cancers. Kisspeptins are proteins encoded by the KISS1 gene that was originally described as a melanoma metastasis suppressor gene. Then, Kisspeptins were discovered as the natural ligands of the G-protein-coupled receptor 54(GPR54) that is also called KISS1R. The KISS1/KISS1R signaling is essential to control Gn RH secretion during puberty and to establish mammalian reproductive function through the hypothalamic-pituitary-gonadal(HPG) axis. Although KISS1primarily plays a suppressive role in the metastasis progression in several cancer types, emerging evidence indicates that the physiological effect of KISS1/KISS1R in cancer metastasis is tissue context-dependent and still controversial. Here, we will discuss the epigenetic mechanism involved in the regulation of KISS1 gene expression, the context-dependent role of KISS1/KISS1R, prometastasis/anti-metastasis signaling pathways of KISS1/KISS1R, and the perspective anticancer therapeutics via targeting KISS1/KISS1R.
基金supported in part by 1K99CA263194 to F.D.,R01CA229307,R35CA253027 to W.W。
文摘Ubiquitination plays critical roles in regulating various physiological events,such as protein degradation,activation,secretion,sorting and trafficking(Dang et al.,2021).The ubiquitination process involves three major steps,catalyzed by ubiquitin-activating enzymes(E1s),ubiquitin-conjugating enzymes(E2s),and ubiquitin ligases(E3s),respectively(Scheffner et al.,1995).
基金supported by the funds from National Natural Science Foundation of China(92253203 and U22A20317)to Y.S.Zhejiang Provincial Natural Science Foundation of China(LD22H300003)to Y.S.+1 种基金Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(2022R01002)to Y.S.a grant from Research Center for Life Science and Human Health,Binjiang Institute of Zhejiang University(ZY202205SMKY007)to Y.S.
文摘Much akin to ubiquitylation,neddylation is catalyzed by a cascade of three enzymes:E1 NEDD8-activating enzyme,E2 NEDD8-conjugating enzyme(UBE2M or UBE2F),and E3 NEDD8 ligases.The best-known neddylation substrates are the members of cullin family,leading to the activation of Cullin-RING ligases,which regulate a variety of downstream biological processes largely via promoting ubiquitylation and subsequent proteasomal degradation of many key signaling proteins.Notably,neddylation enzymes and components of the Cullin-RING ligases are frequently altered in many human cancers and have been validated as promising cancer targets.As such,drug discovery efforts are underway to target neddylation-Cullin-RING ligases with a few selective small molecule inhibitors being advanced into various phases of clinical trials.This review firstly provides a brief introduction to neddylation,then focuses on lung cancer,and summarizes a wealth of current data showing how neddylation-Cullin-RING ligases are altered and affect the growth and survival of lung cancer cells,lung tumorigenesis,lung tumor microenvironment,and inflammatory response.A few reported small molecule inhibitors of neddylation enzymes as well as their activity against lung cancer cells are also summarized,and future perspectives with an ultimate goal of discovering effective treatment of lung cancer via targeting neddylation-Cullin-RING ligases are proposed.
基金We thank Dr. W. Wei as well as the He and Wei lab members for critical discussion and reading of the manuscript. X. Ci received financial supporc from the China Scholarship Council （CSC） （No.201606120241）. X. Dai is supported by National Research Service Award T-32 training grant. This work was partly supported by the National Natural Science Foundation of China No. 31571323 to Y. Li. X. He acknowledges support by NIH （RO1-GM057603） and by Boston Children＇s Hospital Intellectual and Developmental Disabili- ties Research Center （P30 HD-18655）. X. He is an American Cancer Society Research Professor.
文摘Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmem- brane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled （FZD） receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin f-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiqui- tinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phos- phorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regu- lation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3.
