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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, and interested parties Long press or scan the QR code below to follow us.
iNatureKDM6A is a histone demethylase, which is frequently mutated in bladder cancer (BCa).
However, the role of KDM6A in the progression of bladder cancer and the detailed molecular mechanism are still unknown.
On May 18, 2021, Zou Yongxin and Shi Benkang from Shandong University published an online research paper entitled "KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1" in Molecular Cancer (IF=15.
30).
The study showed that KDM6A inhibited Mobility and aggressiveness of BCa cells.
Mechanistically speaking, KDM6A promotes the transcription of ARHGDIB by demethylating H3K27me2/3, leading to the inhibition of Rac1.
EZH2 catalyzes the methylation of H3K27 to silence the expression of ARHGDIB, while EZH2 inhibitors can neutralize the metastasis caused by KDM6A deficiency.
In addition, this study proved that FOXA1 directly binds to the KDM6A promoter, and thus activates KDM6A, resulting in a decrease in metastatic potential.
In summary, the study found that the key role of the FOXA1-KDM6A-ARHGDIB axis in suppressing BCa malignancies has been established, and KDM6A and EZH2 have been identified as potential therapeutic targets in the management of BCa.
Bladder cancer (BCa) has become the tenth most common malignant tumor in the world, with high morbidity and mortality.
Approximately 75% of patients initially diagnosed with BCa have non-muscle invasive bladder cancer (NMIBC), and 25% have muscle invasive bladder cancer (MIBC).
Among those patients with NMIBC (carcinoma in situ [CIS]/pTa/pT1), up to 30% of patients have experienced the development of MIBC, and the 5-year recurrence-free survival rate of MIBC of pT2 is 74%, for PT3 Is 52% and pT4 is 36%.
Although about 50-60% of MIBC patients can achieve an objective response, many patients are still resistant to first-line treatment.
With the rapid development of Bca gene mutation and comprehensive sequencing of genomic expression, multiple common mutated genes, such as tumor protein p53 (TP53), fibroblast growth factor receptor 3 (FGFR3) and phosphatidylinositol-4,5- Bisphosphate 3-kinase catalytic subunit α (PIK3CA) has been identified and fully studied.
However, there is still no reliable target to detect, treat or predict BCa.
Therefore, a more detailed understanding of the occurrence and development of BCa is essential for the clinical management of BCa.
Post-translational modification (PTM) of histones is considered an important mechanism for regulating gene transcription.
Abnormal histone modifications have been widely involved in the pathogenesis of several human diseases, and some of them have been shown to be potential diagnostic biomarkers or therapeutic targets.
Lysine demethylase 6A (KDM6A), belonging to the family of enzymes containing the JmjC domain, mediates the demethylation of H3K27me2 / 3, thus leading to transcriptional activation.
KDM6A plays a vital role in embryonic development.
The de novo mutation of KDM6A is related to Kabuki syndrome, which is a rare congenital abnormal syndrome characterized by intellectual disability, growth retardation, and a variety of congenital abnormalities.
Somatic mutations of KDM6A have been found in a wide range of human cancers, including multiple myeloma, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, acute lymphoid leukemia, prostate cancer, medulloblastoma, and pancreatic adenocarcinoma.
Although KDM6A mutations have been identified in a variety of cancers, the frequency of mutations varies greatly.
KDM6A has the highest mutation frequency in BCa.
It was found that nearly half of NMIBC and a quarter of MIBC cases had KDM6A inactivation or deleterious mutations.
Whether KDM6A inhibits or promotes tumorigenesis and progression depends on the type of cancer and its interacting transcription factors.
Although KDM6A plays an important role in the tumorigenesis of BCa, little is known about its function and the detailed mechanism in tumor progression and metastasis.
In this study, it was found that KDM6A inhibited the proliferation of monolayer cells in a cell-type-specific manner and reduced the chemotaxis of macrophages in BCa cells.
In addition, this study shows that KDM6A inhibits the migration and invasion of BCa cells in vitro and metastasis in vivo, and low expression of KDM6A is associated with poor prognosis of BCa patients.
Importantly, this study proved that KDM6A epigenetically activates the transcription of Rho GDP dissociation inhibitor β (ARHGDIB) and thus inhibits Rac family small GTPase 1 (Rac1) to exert anti-tumor effects (Rac family small GTPase 1 is in tumor cell movement , Play an important role in invasiveness and metastasis).
In addition, the study found that FOXA1 was recruited to the promoter of the KDM6A gene and promoted its transcription in BCa cells.
Together, the findings of the study established the key role of the FOXA1-KDM6A-ARHGDIB axis in BCa metastasis, thus suggesting the potential therapeutic significance in the management of BCa patients in the future.
Reference message: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-021-01369-9
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, and interested parties Long press or scan the QR code below to follow us.
iNatureKDM6A is a histone demethylase, which is frequently mutated in bladder cancer (BCa).
However, the role of KDM6A in the progression of bladder cancer and the detailed molecular mechanism are still unknown.
On May 18, 2021, Zou Yongxin and Shi Benkang from Shandong University published an online research paper entitled "KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1" in Molecular Cancer (IF=15.
30).
The study showed that KDM6A inhibited Mobility and aggressiveness of BCa cells.
Mechanistically speaking, KDM6A promotes the transcription of ARHGDIB by demethylating H3K27me2/3, leading to the inhibition of Rac1.
EZH2 catalyzes the methylation of H3K27 to silence the expression of ARHGDIB, while EZH2 inhibitors can neutralize the metastasis caused by KDM6A deficiency.
In addition, this study proved that FOXA1 directly binds to the KDM6A promoter, and thus activates KDM6A, resulting in a decrease in metastatic potential.
In summary, the study found that the key role of the FOXA1-KDM6A-ARHGDIB axis in suppressing BCa malignancies has been established, and KDM6A and EZH2 have been identified as potential therapeutic targets in the management of BCa.
Bladder cancer (BCa) has become the tenth most common malignant tumor in the world, with high morbidity and mortality.
Approximately 75% of patients initially diagnosed with BCa have non-muscle invasive bladder cancer (NMIBC), and 25% have muscle invasive bladder cancer (MIBC).
Among those patients with NMIBC (carcinoma in situ [CIS]/pTa/pT1), up to 30% of patients have experienced the development of MIBC, and the 5-year recurrence-free survival rate of MIBC of pT2 is 74%, for PT3 Is 52% and pT4 is 36%.
Although about 50-60% of MIBC patients can achieve an objective response, many patients are still resistant to first-line treatment.
With the rapid development of Bca gene mutation and comprehensive sequencing of genomic expression, multiple common mutated genes, such as tumor protein p53 (TP53), fibroblast growth factor receptor 3 (FGFR3) and phosphatidylinositol-4,5- Bisphosphate 3-kinase catalytic subunit α (PIK3CA) has been identified and fully studied.
However, there is still no reliable target to detect, treat or predict BCa.
Therefore, a more detailed understanding of the occurrence and development of BCa is essential for the clinical management of BCa.
Post-translational modification (PTM) of histones is considered an important mechanism for regulating gene transcription.
Abnormal histone modifications have been widely involved in the pathogenesis of several human diseases, and some of them have been shown to be potential diagnostic biomarkers or therapeutic targets.
Lysine demethylase 6A (KDM6A), belonging to the family of enzymes containing the JmjC domain, mediates the demethylation of H3K27me2 / 3, thus leading to transcriptional activation.
KDM6A plays a vital role in embryonic development.
The de novo mutation of KDM6A is related to Kabuki syndrome, which is a rare congenital abnormal syndrome characterized by intellectual disability, growth retardation, and a variety of congenital abnormalities.
Somatic mutations of KDM6A have been found in a wide range of human cancers, including multiple myeloma, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, acute lymphoid leukemia, prostate cancer, medulloblastoma, and pancreatic adenocarcinoma.
Although KDM6A mutations have been identified in a variety of cancers, the frequency of mutations varies greatly.
KDM6A has the highest mutation frequency in BCa.
It was found that nearly half of NMIBC and a quarter of MIBC cases had KDM6A inactivation or deleterious mutations.
Whether KDM6A inhibits or promotes tumorigenesis and progression depends on the type of cancer and its interacting transcription factors.
Although KDM6A plays an important role in the tumorigenesis of BCa, little is known about its function and the detailed mechanism in tumor progression and metastasis.
In this study, it was found that KDM6A inhibited the proliferation of monolayer cells in a cell-type-specific manner and reduced the chemotaxis of macrophages in BCa cells.
In addition, this study shows that KDM6A inhibits the migration and invasion of BCa cells in vitro and metastasis in vivo, and low expression of KDM6A is associated with poor prognosis of BCa patients.
Importantly, this study proved that KDM6A epigenetically activates the transcription of Rho GDP dissociation inhibitor β (ARHGDIB) and thus inhibits Rac family small GTPase 1 (Rac1) to exert anti-tumor effects (Rac family small GTPase 1 is in tumor cell movement , Play an important role in invasiveness and metastasis).
In addition, the study found that FOXA1 was recruited to the promoter of the KDM6A gene and promoted its transcription in BCa cells.
Together, the findings of the study established the key role of the FOXA1-KDM6A-ARHGDIB axis in BCa metastasis, thus suggesting the potential therapeutic significance in the management of BCa patients in the future.
Reference message: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-021-01369-9
