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iNature colorectal cancer (CRC) is the third most commonly diagnosed cancer, and its fatality rate ranks third among all cancer types.
It is a multifactorial cancer with multiple genetic and epigenetic aberrations.
Early screening through colonoscopy and understanding of molecular mechanisms can help reduce the incidence and mortality of colorectal cancer.
Further exploration of genes and signaling pathways related to colorectal cancer will help determine new prognosis and therapeutic targets.
On March 15, 2021, the Chen Shuai team of Sun Yat-sen University published a research paper entitled "Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells" in Advanced Science (IF=16).
Genomic shRNA screening identified Dyskerin pseudouridine synthase 1 (DKC1) as a previously unknown key regulator that promotes the proliferation of colorectal cancer cells.
The forced expression of DKC1, instead of its catalytically inactive mutant D125A, promotes cell growth in vitro and in vivo.
DKC1 knockdown or its inhibitor pyrazofurin attenuates cell proliferation.
Proteomics, immunoprecipitation RNA (RIP)-SEQ and RNA decay analysis showed that DKC1 binds and stabilizes the mRNA expression of several ribosomal proteins (RPs), including RPL10A, RPL22L1, RPL34 and RPS3.
DKC1 depletion significantly accelerates the mRNA attenuation of these RPs, thereby mediating the carcinogenic function of DKC1.
Interestingly, these DKC1-regulated RPs also interact with HRAS and inhibit the RAS / RAF / MEK / ERK signaling pathway.
The combination of pyrazofurin and trametinib synergistically inhibits the growth of colorectal cancer cells in vitro and in vivo.
In addition, compared with adjacent normal tissues, DKC1 was significantly up-regulated in colorectal cancer tissues.
Colorectal cancer patients have higher DKC1 expression and consistently poor overall survival and progression-free survival.
In summary, these data indicate that DKC1 is an important gene and candidate therapeutic target for colorectal cancer.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer, and its fatality rate ranks third among all cancer types.
It is a multifactorial cancer with multiple genetic and epigenetic aberrations.
Early screening through colonoscopy and understanding of molecular mechanisms can help reduce the incidence and mortality of colorectal cancer.
For example, antibodies against vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) have been developed and widely used to treat CRC.
Further exploration of genes and signaling pathways related to colorectal cancer will help determine new prognosis and therapeutic targets.
The dyskerin pseudouridine synthase 1 (DKC1) gene is mutated in congenital dyskeratosis and encodes the evolutionarily conserved RNA binding protein dyskerin.
Dyskerin is a component of telomerase ribonucleoprotein and is related to three highly conserved proteins (NOP10, NHP2, GAR1).
The dyskerin protein complex is also involved in the formation of a small nucleolar ribonucleoprotein (snoRNP) complex.
The complex binds to H/ACA small nucleolar RNA.
Dyskerin acts as an RNA-guided pseudouridine synthase, catalyzing the isomerization of uridine (U) nucleosides in its target RNA to pseudouridine (Ψ) nucleosides.
In addition, recent reports indicate that the imbalance of DKC1 expression in various human cancers can alter the growth or metastasis of cancer cells, and is related to the prognosis of patients.
In this study, DKC1 was identified as the essential highest-scoring gene in colorectal cancer through genome-wide shRNA screening.
DKC1 binds and stabilizes the mRNA of certain ribosomal proteins in a manner dependent on its pseudouridine synthase activity, thereby promoting the progression of colorectal cancer in vitro and in vivo.
The ribosomal protein targeting DKC1 interacts with HRAS and inhibits HRAS, thereby attenuating the downstream RAF/MEK/ERK pathway.
The combination of DKC1 inhibitor pyrazofurin (PF) and MEK1/2 inhibitor trametinib can synergistically inhibit the growth of colorectal cancer.
In addition, the higher expression of DKC1 in colorectal cancer is associated with a poor prognosis, which indicates that DKC1 is a candidate treatment target for CRC.
Reference message: https://onlinelibrary.
wiley.
com/doi/10.
1002/advs.
202004344
It is a multifactorial cancer with multiple genetic and epigenetic aberrations.
Early screening through colonoscopy and understanding of molecular mechanisms can help reduce the incidence and mortality of colorectal cancer.
Further exploration of genes and signaling pathways related to colorectal cancer will help determine new prognosis and therapeutic targets.
On March 15, 2021, the Chen Shuai team of Sun Yat-sen University published a research paper entitled "Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells" in Advanced Science (IF=16).
Genomic shRNA screening identified Dyskerin pseudouridine synthase 1 (DKC1) as a previously unknown key regulator that promotes the proliferation of colorectal cancer cells.
The forced expression of DKC1, instead of its catalytically inactive mutant D125A, promotes cell growth in vitro and in vivo.
DKC1 knockdown or its inhibitor pyrazofurin attenuates cell proliferation.
Proteomics, immunoprecipitation RNA (RIP)-SEQ and RNA decay analysis showed that DKC1 binds and stabilizes the mRNA expression of several ribosomal proteins (RPs), including RPL10A, RPL22L1, RPL34 and RPS3.
DKC1 depletion significantly accelerates the mRNA attenuation of these RPs, thereby mediating the carcinogenic function of DKC1.
Interestingly, these DKC1-regulated RPs also interact with HRAS and inhibit the RAS / RAF / MEK / ERK signaling pathway.
The combination of pyrazofurin and trametinib synergistically inhibits the growth of colorectal cancer cells in vitro and in vivo.
In addition, compared with adjacent normal tissues, DKC1 was significantly up-regulated in colorectal cancer tissues.
Colorectal cancer patients have higher DKC1 expression and consistently poor overall survival and progression-free survival.
In summary, these data indicate that DKC1 is an important gene and candidate therapeutic target for colorectal cancer.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer, and its fatality rate ranks third among all cancer types.
It is a multifactorial cancer with multiple genetic and epigenetic aberrations.
Early screening through colonoscopy and understanding of molecular mechanisms can help reduce the incidence and mortality of colorectal cancer.
For example, antibodies against vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) have been developed and widely used to treat CRC.
Further exploration of genes and signaling pathways related to colorectal cancer will help determine new prognosis and therapeutic targets.
The dyskerin pseudouridine synthase 1 (DKC1) gene is mutated in congenital dyskeratosis and encodes the evolutionarily conserved RNA binding protein dyskerin.
Dyskerin is a component of telomerase ribonucleoprotein and is related to three highly conserved proteins (NOP10, NHP2, GAR1).
The dyskerin protein complex is also involved in the formation of a small nucleolar ribonucleoprotein (snoRNP) complex.
The complex binds to H/ACA small nucleolar RNA.
Dyskerin acts as an RNA-guided pseudouridine synthase, catalyzing the isomerization of uridine (U) nucleosides in its target RNA to pseudouridine (Ψ) nucleosides.
In addition, recent reports indicate that the imbalance of DKC1 expression in various human cancers can alter the growth or metastasis of cancer cells, and is related to the prognosis of patients.
In this study, DKC1 was identified as the essential highest-scoring gene in colorectal cancer through genome-wide shRNA screening.
DKC1 binds and stabilizes the mRNA of certain ribosomal proteins in a manner dependent on its pseudouridine synthase activity, thereby promoting the progression of colorectal cancer in vitro and in vivo.
The ribosomal protein targeting DKC1 interacts with HRAS and inhibits HRAS, thereby attenuating the downstream RAF/MEK/ERK pathway.
The combination of DKC1 inhibitor pyrazofurin (PF) and MEK1/2 inhibitor trametinib can synergistically inhibit the growth of colorectal cancer.
In addition, the higher expression of DKC1 in colorectal cancer is associated with a poor prognosis, which indicates that DKC1 is a candidate treatment target for CRC.
Reference message: https://onlinelibrary.
wiley.
com/doi/10.
1002/advs.
202004344
