Uveal melanoma is the most common intraocular cancer in the adult eye.R183 and Q209 were found to be mutational hotspots in exon 4 and exon 5 of GNAQ and GNA11 in Caucasians.However,only a few studies have reported so...Uveal melanoma is the most common intraocular cancer in the adult eye.R183 and Q209 were found to be mutational hotspots in exon 4 and exon 5 of GNAQ and GNA11 in Caucasians.However,only a few studies have reported somaticmutations in GNAQ or GNA11 in uveal melanoma in Chinese.We extracted somatic DNA from paraffin-embedded biopsies of 63 Chinese uveal melanoma samples and sequenced the entire coding regions of exons 4 and 5 in GNAQ and GNA11.The results showed that 33%of Chinese uveal melanoma samples carried Q209 mutations while none had R183 mutation in GNAQ or GNA11.In addition,seven novel missense somatic mutations in GNAQ(Y192C,F194L,P170S,D236N,L232F,V230A,and M227I)and four novel missense somatic mutations in GNA11(R166C,I200T,S225F,and V206M)were found in our study.The high mutation frequency of Q209 and the novel missense mutations detected in this study suggest that GNAQ and GNA11 are common targets for somatic mutations in Chinese uveal melanoma.展开更多
Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions.In search of gen...Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions.In search of genetic vulnerability for UM,we found that inhibition of euchromatic histone lysine methyltransferase 2(EHMT2)expression or activity significantly reduced the proliferation and migration capacity of cancer cells.Notably,elevated expression of EHMT2 had been validated in UM samples.Furthermore,Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T stage.Chromatin immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of EHMT2.Its transcription was suppressed by EHMT2 in a methyltransferasedependent pattern in GNAQ/11-mutant UM cells,leading to elevated RhoA activity.Rescuing constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic phenotypes.Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth,suggesting the driver role of these two key molecules.In summary,our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.展开更多
基金This work was supported by State Key Laboratory of Ophthalmology(Zhongshan Ophthalmic Center,Sun Yat-Sen University),“100 talents plan”from Sun Yatsen University,the Open Research Funds of the State Key Laboratory of Ophthalmology(2017KF05)Funds of the Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science(2017B030314025)+1 种基金Medical Research Fund of Guangdong Province(No.A2018337)Guangzhou Institute of Pediatrics/GuangzhouWomen and Children’s Medical Center(No.IP-2018-002).
文摘Uveal melanoma is the most common intraocular cancer in the adult eye.R183 and Q209 were found to be mutational hotspots in exon 4 and exon 5 of GNAQ and GNA11 in Caucasians.However,only a few studies have reported somaticmutations in GNAQ or GNA11 in uveal melanoma in Chinese.We extracted somatic DNA from paraffin-embedded biopsies of 63 Chinese uveal melanoma samples and sequenced the entire coding regions of exons 4 and 5 in GNAQ and GNA11.The results showed that 33%of Chinese uveal melanoma samples carried Q209 mutations while none had R183 mutation in GNAQ or GNA11.In addition,seven novel missense somatic mutations in GNAQ(Y192C,F194L,P170S,D236N,L232F,V230A,and M227I)and four novel missense somatic mutations in GNA11(R166C,I200T,S225F,and V206M)were found in our study.The high mutation frequency of Q209 and the novel missense mutations detected in this study suggest that GNAQ and GNA11 are common targets for somatic mutations in Chinese uveal melanoma.
基金supported by the Science and Technology Commission of Shanghai(20DZ2270800,China)the National Natural Science Foundation of China(grants 82073889)+1 种基金the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210900,China)China Postdoctoral Science Foundation(2022M722120,China)and Shanghai Sailing Program(22YF1422800,China)。
文摘Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions.In search of genetic vulnerability for UM,we found that inhibition of euchromatic histone lysine methyltransferase 2(EHMT2)expression or activity significantly reduced the proliferation and migration capacity of cancer cells.Notably,elevated expression of EHMT2 had been validated in UM samples.Furthermore,Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T stage.Chromatin immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of EHMT2.Its transcription was suppressed by EHMT2 in a methyltransferasedependent pattern in GNAQ/11-mutant UM cells,leading to elevated RhoA activity.Rescuing constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic phenotypes.Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth,suggesting the driver role of these two key molecules.In summary,our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.
