Radiotherapy remains a mainstay of cancer treatment.However,radiotherapy can also elicit acute and chronic adverse effects,including dermal inflammation and skin fibrosis.A comprehensive understanding of the underlyin...Radiotherapy remains a mainstay of cancer treatment.However,radiotherapy can also elicit acute and chronic adverse effects,including dermal inflammation and skin fibrosis.A comprehensive understanding of the underlying fibrotic processes remains elusive,and currently,no established treatment options exist.Canonical Wnt signaling has emerged as a significant player in fibrotic conditions.The Dickkopf(DKK)protein family comprises key modulators of Wnt signaling.To define the function of DKK3 in radiation-induced skin damage,we combined complementary in vivo and in vitro approaches,including a 3D human skin model,mice with cell-type-specific Dkk3 deletions,and irradiated human skin specimens.Our study revealed the pivotal role of DKK3 in regulating the response of the skin to radiation,with diminished DKK3 significantly mitigating radiation-induced skin damage.We found that radiation increases DKK3 expression in basal keratinocytes,leading to elevated ROS levels,TGF-β-mediated Wnt activation,epidermal hyperplasia,and subsequent skin fibrosis.Increased keratinocyte expression of DKK3 also drives macrophage polarization toward a CD163highCD206high profibrotic M2 phenotype,activating myofibroblasts and leading to fibrosis.Notably,DKK3 deficiency in keratinocytes markedly reduces radiation-induced dermal hyperplasia and fibrosis,identifying DKK3 as a key regulator of cutaneous radiation responses.These findings position DKK3 as a promising upstream modulator of TGF-βsignaling for mitigating radiation-induced dermatitis and fibrosis,with potential relevance to other fibrotic diseases.展开更多
Enolase 2(ENO2)is a key glycolytic enzyme in the metabolic process of glycolysis,but its potential function in pancreatic ductal adenocarcinoma(PDAC)is unclear.In this study,we observed a significant overexpression of...Enolase 2(ENO2)is a key glycolytic enzyme in the metabolic process of glycolysis,but its potential function in pancreatic ductal adenocarcinoma(PDAC)is unclear.In this study,we observed a significant overexpression of ENO2 in PDAC tissues,and its expression was correlated with metastasis and poor prognosis in PDAC patients.K394 was identified as a major acetylation site in ENO2 that regulates its enzymatic activity,cell metabolism and PDAC progression.Knockdown of ENO2 suppressed tumor growth and liver metastasis in PDAC.Re-expression of wild-type(WT)ENO2,but not the K394 acetylation mimetic mutant,could reverse the decreased tumor malignancy.We further characterized histone deacetylase 3(HDAC3)and P300/CBP-associated factor(PCAF)as the potential deacetylase and acetyltransferase for ENO2,respectively.HDAC3-mediated deacetylation was shown to lead to ENO2 activation and enhancement of glycolysis.Importantly,insulin-like growth factor-1(IGF-1)was found to decrease K394 acetylation and stimulate ENO2 activity in a dose-and time-dependent manner.The PI3K/AKT/mTOR pathway facilitated the phosphorylation of HDAC3 on S424,which promoted K394 deacetylation and activation of ENO2.Linsitinib,an oral small-molecule inhibitor of IGF-1R,could inhibit IGF-1-induced ENO2 deacetylation by HDAC3 and the PI3K/AKT/mTOR pathway.Furthermore,linsitinib showed a different effect on the growth and metastasis of PDAC depending on the overexpression of WT versus K394-mutant ENO2.Our results reveal a novel mechanism by which acetylation negatively regulates ENO2 activity in the metastasis of PDAC by modulating glycolysis.Blockade of IGF-1-induced ENO2 deacetylation represents a promising strategy to prevent the development of PDAC.展开更多
基金Open Access funding enabled and organized by Projekt DEAL.
文摘Radiotherapy remains a mainstay of cancer treatment.However,radiotherapy can also elicit acute and chronic adverse effects,including dermal inflammation and skin fibrosis.A comprehensive understanding of the underlying fibrotic processes remains elusive,and currently,no established treatment options exist.Canonical Wnt signaling has emerged as a significant player in fibrotic conditions.The Dickkopf(DKK)protein family comprises key modulators of Wnt signaling.To define the function of DKK3 in radiation-induced skin damage,we combined complementary in vivo and in vitro approaches,including a 3D human skin model,mice with cell-type-specific Dkk3 deletions,and irradiated human skin specimens.Our study revealed the pivotal role of DKK3 in regulating the response of the skin to radiation,with diminished DKK3 significantly mitigating radiation-induced skin damage.We found that radiation increases DKK3 expression in basal keratinocytes,leading to elevated ROS levels,TGF-β-mediated Wnt activation,epidermal hyperplasia,and subsequent skin fibrosis.Increased keratinocyte expression of DKK3 also drives macrophage polarization toward a CD163highCD206high profibrotic M2 phenotype,activating myofibroblasts and leading to fibrosis.Notably,DKK3 deficiency in keratinocytes markedly reduces radiation-induced dermal hyperplasia and fibrosis,identifying DKK3 as a key regulator of cutaneous radiation responses.These findings position DKK3 as a promising upstream modulator of TGF-βsignaling for mitigating radiation-induced dermatitis and fibrosis,with potential relevance to other fibrotic diseases.
基金supported by the National Key Research and Development Program of China(No.2017YFC1308604)the Shanghai Program for Innovative Research Team in Universities,the National Natural Science Foundation of China(No.81802903,81672820,81772563,81930074 and 81872356)+2 种基金the NSFC Program of International Cooperation and Exchanges(No.81120108016)the National Key Basic Research Program of China(No.2013CB910500 and 2014CB542101)China National Key Projects for Infectious Disease(No.2012ZX10002-012).
文摘Enolase 2(ENO2)is a key glycolytic enzyme in the metabolic process of glycolysis,but its potential function in pancreatic ductal adenocarcinoma(PDAC)is unclear.In this study,we observed a significant overexpression of ENO2 in PDAC tissues,and its expression was correlated with metastasis and poor prognosis in PDAC patients.K394 was identified as a major acetylation site in ENO2 that regulates its enzymatic activity,cell metabolism and PDAC progression.Knockdown of ENO2 suppressed tumor growth and liver metastasis in PDAC.Re-expression of wild-type(WT)ENO2,but not the K394 acetylation mimetic mutant,could reverse the decreased tumor malignancy.We further characterized histone deacetylase 3(HDAC3)and P300/CBP-associated factor(PCAF)as the potential deacetylase and acetyltransferase for ENO2,respectively.HDAC3-mediated deacetylation was shown to lead to ENO2 activation and enhancement of glycolysis.Importantly,insulin-like growth factor-1(IGF-1)was found to decrease K394 acetylation and stimulate ENO2 activity in a dose-and time-dependent manner.The PI3K/AKT/mTOR pathway facilitated the phosphorylation of HDAC3 on S424,which promoted K394 deacetylation and activation of ENO2.Linsitinib,an oral small-molecule inhibitor of IGF-1R,could inhibit IGF-1-induced ENO2 deacetylation by HDAC3 and the PI3K/AKT/mTOR pathway.Furthermore,linsitinib showed a different effect on the growth and metastasis of PDAC depending on the overexpression of WT versus K394-mutant ENO2.Our results reveal a novel mechanism by which acetylation negatively regulates ENO2 activity in the metastasis of PDAC by modulating glycolysis.Blockade of IGF-1-induced ENO2 deacetylation represents a promising strategy to prevent the development of PDAC.
