Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression,yet how this process is regulated by oncogenic signal remains largely unknown.Here,we unveil that non-canonical activation o...Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression,yet how this process is regulated by oncogenic signal remains largely unknown.Here,we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m^(6)A reader YTHDC1 in lung cancer.Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing,specifically triggering RBM4 splicing from the full isoform(RBM4-FL)to the short isoform(RBM4-S)in a kinase-independent manner.展开更多
Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors.However,the detailed mechanisms by which tumor cells evade premature senescence to mali...Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors.However,the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive.Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma(ESCC)cells by dictating the activity of LKB1,a critical governor of cancer metabolism.The level of RBM4 was specifically elevated in ESCC compared to normal tissues,and RBM4 overexpression promoted the malignant phenotype.RBM4 contributed to overcome H-RAS-or doxorubicin-induced senescence,while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade.Mechanistically,RBM4 competitively bound LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex,subsequently recruiting the E3 ligase TRIM26 to LKB1,promoting LKB1 ubiquitination and degradation in nucleus.Therefore,such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism.Clinically,the ESCC patients with high RBM4 and low LKB1 have significantly worse overall survival than those with low RBM4 and high LKB1.The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells to glutaminase inhibitor CB-839,providing a novel insight into mechanisms underlying the glutamine-dependency to improve the efficacy of glutamine inhibitors in ESCC therapeutics.展开更多
Alternative splicing is a critical process to generate protein diversity.However,whether and how alternative splicing regulates autophagy remains largely elusive.Here we systematically identify the splicing factor SRS...Alternative splicing is a critical process to generate protein diversity.However,whether and how alternative splicing regulates autophagy remains largely elusive.Here we systematically identify the splicing factor SRSF1 as an autophagy suppressor.Specifically,SRSF1 inhibits autophagosome formation by reducing the accumulation of LC3-ⅡI and numbers of autophagosomes in different cell lines.Mechanistically,SRSF1 promotes the splicing of the long isoform of Bcl-x that interacts with Beclinl,thereby dissociating the Beclin1-PIK3C3 complex.In addition,SRSF1 also directly interacts with PIK3C3 to disrupt the interaction between Beclinl and PIK3C3.Consequently,the decrease of SRSF1 stabilizes the Beclinl and PIK3C3 complex and activates autophagy.Interestingly,SRSF1 can be degraded by starvation-and oxidative stresses-induced autophagy through interacting with LC3-Ⅱ,whereas reduced SRSF1 further promotes autophagy.This positive feedback is critical to inhibiting Gefitinib-resistant cancer cell progression both in vitro and in vivo.Consistently,the expression level of SRSF1 is inversely correlated to LC3 level in clinical cancer samples.Our study not only provides mechanistic insights of alternative splicing in autophagy regulation but also discovers a new regulatory role of SRSF1 in tumorigenesis,thereby offering a novel avenue for potential cancer therapeutics.展开更多
Increasing evidence suggests that deregulated RNA splicing factors play critical roles in tumorigenesis;however,their specific involvement in colon cancer remains largely unknown.Here we report that the splicing facto...Increasing evidence suggests that deregulated RNA splicing factors play critical roles in tumorigenesis;however,their specific involvement in colon cancer remains largely unknown.Here we report that the splicing factor RBM25 is overexpressed in colon cancer,and this increased expression correlates with a poor prognosis of patients with colon cancer.Functionally,RBM25 ablation suppresses the growth of colon cancer cells both in vitro and in vivo.Mechanistically,our transcriptome-wide analysis of splicing events revealed that RBM25 regulates a large number of cancer-related alternative splicing events across the human genome in colon cancer.Particularly,RBM25 regulates the splicing of MNK2 by interacting with the poly G rich region in exon 14a,thereby inhibiting the selection of the proximal 3'splice site(ss),resulting in the production of the oncogenic short isoform,MNK2b.Knockdown of RBM25 leads to an increase in the MNK2a isoform and a decrease in the MNK2b isoform.Importantly,re-expression of MNK2b or blocking the 3′ss of the alternative exon 14a with ASO partially reverses the RBM25 knockdown mediated tumor suppression.Moreover,MNK2b levels were significantly increased in colon cancer tissues,which is positively correlated with the expression level of RBM25.Collectively,our findings uncover the critical role of RBM25 as a key splicing factor in colon cancer,suggesting its potential as a prognostic marker and therapeutic target.展开更多
基金We thank Quentin Liu’s lab members for their critical comments and technical support.We thank Eric W.-F.Lam for his critical reading of the manuscript and insightful suggestions.This research work was supported by the National Natural Science Foundation of China(No.81820108024 to Q.L.,No.81630005 to Q.L.,No.81830088 to Y.W.,No.81873441 to B.-L.J.,No.82103659 to S.-S.L.,No.8210113819 to Y.-F.Q.,No.81972786 to J.X.,No.82003141 to F.P.,No.82002960 to B.C.,No.31801100 to X.-.D.D.)National Key R&D Program of China(2019YFA0110300 to Q.L.and 2017YFA0505600-04 to Q.L.)+12 种基金Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China(No.IRT_17R15)Innovative Research Team in University of Liaoning(No.LT2017001 to Q.L.)Heilongjiang Postdoctoral Fund(No.LBH-Z20074 to S.-S.L.)Harbin Medical University Doctor Green Seedling Ground-breaking Project(No.QMPT-1909 to S.-S.L.)the Natural Science Foundation of Liaoning(No.2019-BS-081 to F.P.)the“Seedling cultivation”program for young scientific and technological talents of Liaoning(No.LZ2020044 to F.P.,No.LZ2019067 to B.C.)Dalian Science and Technology program-The central government guiding local funding projects for scientific and technological development(2021 to F.P.)Dalian High-level Talents Innovation Support Program-Young Science and Technology Star(2021RQ004 to B.C.)the program for climbing Scholars of Liaoning,the Science and Technology Innovation Foundation of Dalian(No.2020JJ25CY008 to Q.L.)International Scientific and Technological Cooperation of Dalian(2015F11GH095 to Q.L.)the Natural Science Foundation of Guangdong(2016A030311038 and 2017A030313608 to Q.L.)the Science and Technology Planning Project of Guangzhou(No.201804020044 to Q.L.)the Scientific Research Project of Guangzhou(No.201904010492 to B.-L.J.).
文摘Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression,yet how this process is regulated by oncogenic signal remains largely unknown.Here,we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m^(6)A reader YTHDC1 in lung cancer.Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing,specifically triggering RBM4 splicing from the full isoform(RBM4-FL)to the short isoform(RBM4-S)in a kinase-independent manner.
基金supported by the National Natural Science Foundation of China (82225034,81830088 to Y.W.,82103148 to Y.Q.81872247 to W.Z.)+4 种基金the Department of Science and Technology of Liaoning Province (2021JH6/10500160 to Y.W.)the Basic Scientific Research Project of Education Department of Liaoning Province (LJKQZ2021104 to Y.Q.)the Science and Technology Innovation Talent Support Program of Dalian (2022RQ056 Y.Q.)the Science and Technology Innovation Foundation of Dalian (2022JJ11CG009 to Y.W.)Dalian High Level Talents Renovation Supporting Program (2019RQ097 to W.Z.).
文摘Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors.However,the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive.Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma(ESCC)cells by dictating the activity of LKB1,a critical governor of cancer metabolism.The level of RBM4 was specifically elevated in ESCC compared to normal tissues,and RBM4 overexpression promoted the malignant phenotype.RBM4 contributed to overcome H-RAS-or doxorubicin-induced senescence,while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade.Mechanistically,RBM4 competitively bound LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex,subsequently recruiting the E3 ligase TRIM26 to LKB1,promoting LKB1 ubiquitination and degradation in nucleus.Therefore,such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism.Clinically,the ESCC patients with high RBM4 and low LKB1 have significantly worse overall survival than those with low RBM4 and high LKB1.The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells to glutaminase inhibitor CB-839,providing a novel insight into mechanisms underlying the glutamine-dependency to improve the efficacy of glutamine inhibitors in ESCC therapeutics.
基金This work was supported by the National Natural Science Foundation of China(81830088,81422038,91540110,and 31471235 to Y.W.,81872247 and 31400726 to W.Z.)the Department of Education of Liaoning Province(the"Liaoning Supports High Level Talents Innovation and Entrepreneurship Program"XLYC1802067 to Y.W.)+1 种基金the Department of Science and Technology of Dalian City(the HDalian Supports High Level Talents Innovation and Entrepreneurship Program" 2016RJ02 to Y.W.)the Newton Advanced Fellowship from the Academy of Medical Sciences in UK(JXR11831 to Y.W.).
文摘Alternative splicing is a critical process to generate protein diversity.However,whether and how alternative splicing regulates autophagy remains largely elusive.Here we systematically identify the splicing factor SRSF1 as an autophagy suppressor.Specifically,SRSF1 inhibits autophagosome formation by reducing the accumulation of LC3-ⅡI and numbers of autophagosomes in different cell lines.Mechanistically,SRSF1 promotes the splicing of the long isoform of Bcl-x that interacts with Beclinl,thereby dissociating the Beclin1-PIK3C3 complex.In addition,SRSF1 also directly interacts with PIK3C3 to disrupt the interaction between Beclinl and PIK3C3.Consequently,the decrease of SRSF1 stabilizes the Beclinl and PIK3C3 complex and activates autophagy.Interestingly,SRSF1 can be degraded by starvation-and oxidative stresses-induced autophagy through interacting with LC3-Ⅱ,whereas reduced SRSF1 further promotes autophagy.This positive feedback is critical to inhibiting Gefitinib-resistant cancer cell progression both in vitro and in vivo.Consistently,the expression level of SRSF1 is inversely correlated to LC3 level in clinical cancer samples.Our study not only provides mechanistic insights of alternative splicing in autophagy regulation but also discovers a new regulatory role of SRSF1 in tumorigenesis,thereby offering a novel avenue for potential cancer therapeutics.
基金supported by the National Key Research and Development Program of China(2022YFA1104002,2023YFE0117500)the National Natural Science Foundation of China(82225034,82273427)+1 种基金the Science and Technology Innovation Talent Support Program of Dalian(2022RJ15,2022JJ11CG009)the Liaoning Revitalization Talents Program(XLYC2202027)。
文摘Increasing evidence suggests that deregulated RNA splicing factors play critical roles in tumorigenesis;however,their specific involvement in colon cancer remains largely unknown.Here we report that the splicing factor RBM25 is overexpressed in colon cancer,and this increased expression correlates with a poor prognosis of patients with colon cancer.Functionally,RBM25 ablation suppresses the growth of colon cancer cells both in vitro and in vivo.Mechanistically,our transcriptome-wide analysis of splicing events revealed that RBM25 regulates a large number of cancer-related alternative splicing events across the human genome in colon cancer.Particularly,RBM25 regulates the splicing of MNK2 by interacting with the poly G rich region in exon 14a,thereby inhibiting the selection of the proximal 3'splice site(ss),resulting in the production of the oncogenic short isoform,MNK2b.Knockdown of RBM25 leads to an increase in the MNK2a isoform and a decrease in the MNK2b isoform.Importantly,re-expression of MNK2b or blocking the 3′ss of the alternative exon 14a with ASO partially reverses the RBM25 knockdown mediated tumor suppression.Moreover,MNK2b levels were significantly increased in colon cancer tissues,which is positively correlated with the expression level of RBM25.Collectively,our findings uncover the critical role of RBM25 as a key splicing factor in colon cancer,suggesting its potential as a prognostic marker and therapeutic target.
