Extracellular overproduction of E7 oncoprotein of Iranian ...
Sarcoma - Cancer Discovery · sarcoma cells to histone deacetylase (HDAC) inhibitors, the...
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386 | CANCER DISCOVERY MAY 2012 www.aacrjournals.org Major finding: ROR1 promotes EGF-induced, ERBB3-dependent PI3K pathway activation. Clinical relevance: Gefitinib-resistant lung cancer cells are sensitive to ROR1 inhibition. Impact: Targeting ROR1 may be an effective strategy for lung cancer treatment. Lung Cancer ROR1 MEDIATES EGFR SIGNALING IN LUNG ADENOCARCINOMA (EGFR) and led to activation of the PI3K pathway by pro- moting the activation of ERBB3 by EGFR and by phosphor- ylating SRC. These findings suggest that ROR1 sustains a favorable balance of prosurvival signaling and mediates the downstream effects of EGF signaling. Therefore, ROR1 may be an attractive therapeutic target in lung adenocarcinomas, which frequently harbor activating EGFR mutations and de- velop secondary resistance mutations following treatment with EGFR inhibitors such as gefitinib. ROR1 knockdown not only suppressed the growth of gefitinib-resistant, EGFR- mutant lung adenocarcinoma cells but also suppressed ge- fitinib-sensitive, EGFR wild-type cells, suggesting that lung adenocarcinoma cells are dependent on ROR1 for survival re- gardless of EGFR mutational status and that targeting ROR1 may be an effective therapeutic strategy for this disease. ≠ Yamaguchi T, Yanagisawa K, Sugiyama R, Hosono Y, Shimada Y, Arima C, et al. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell 2012;21:348–61. Some cancers are dependent on aberrant activation of lineage-specific developmental regulators that drive prolif- eration of particular cell types. Lung adenocarcinomas have previously been shown to be dependent on NK2 homeobox 1 (NKX2-1), a homeodomain transcription factor that plays an essential role in lung development. Yamaguchi and col- leagues sought to characterize the downstream events of NKX2-1 activation by performing microarray analysis of a human peripheral lung epithelial cell line stably expressing NKX2-1 and identified receptor tyrosine kinase-like orphan recep- tor 1 (ROR1) as one of the most highly upregulated genes. Chromatin immunoprecipitation showed that ROR1 is a direct target of NKX2-1, and coexpression of NKX2-1 and ROR1 was observed in a panel of lung adenocarcinoma pa- tient samples. Knockdown of ROR1 inhibited lung adeno- carcinoma growth in vitro and suppressed xenograft tumor growth, indicating that induction of ROR1 by NKX2-1 is re- quired for tumor cell survival. The authors found that ROR1 repressed proapoptotic p38 signaling, and in response to epi- dermal growth factor (EGF), ROR1 bound to EGF receptor these proteins together. ATF2 was required for recruiting SS18–SSX and TLE1 to cAMP-re- sponsive elements, which provides a potential explanation for how SS18–SSX might regulate transcription without being able to directly bind DNA. TLE1 was responsible for incor- porating EZH2 and HDAC1 into the SS18– SSX complex, which was associated with increased histone H3 lysine-27 trimethylation and suppres- sion of ATF2 target gene expression. ATF2 target gene expres- sion could be restored by HDAC inhibition, which inhibited TLE1 recruitment to the SS18–SSX complex. Together, these findings suggest that SS18–SSX couples ATF2 and TLE1 ac- tivity to suppress ATF2 targets and provide a mechanistic rationale for the use of HDAC inhibitors in synovial sarcoma treatment. ≠ Su L, Sampaio AV, Jones KB, Pacheco M, Goytain A, Lin S, et al. Deconstruction of the SS18–SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell 2012;21:333–47. Synovial sarcomas are aggressive soft-tissue tumors frequently occurring near joints that are characterized by a SS18–SSX fusion tran- script resulting from a reciprocal transloca- tion between chromosomes 18 and X. Because of its association with chromatin remodel- ing proteins and the sensitivity of synovial sarcoma cells to histone deacetylase (HDAC) inhibitors, the SS18–SSX oncoprotein is thought to drive epigenetically mediated transcriptional deregulation, but its mechanism of action has remained unknown. To gain insight into the role of SS18–SSX, Su and colleagues immunopre- cipitated SS18–SSX from synovial sarcoma cells and identi- fied interacting proteins via mass spectrometry. Two master transcriptional regulators, activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1) were identified as SS18–SSX interactors and were both required for synovial sarcoma cell growth and colony formation. ATF2 and TLE1 did not interact in the absence of SS18–SSX, sug- gesting that the fusion oncoprotein acts as a scaffold to bring Major finding: SS18–SSX couples ATF2 DNA-binding activity to TLE1-mediated epigenetic repression. Clinical relevance: HDAC inhibitors interfere with TLE1 recruitment and rescue ATF2 target gene expression. Impact: These findings provide insight into the function of the SS18–SSX oncoprotein. Sarcoma SS18–SSX MEDIATES ATF2 TARGET GENE SUPPRESSION IN SYNOVIAL SARCOMA RESEARCH WATCH Cancer Research. on October 23, 2020. © 2012 American Association for cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst March 29, 2012; DOI: 10.1158/2159-8290.CD-RW2012-042
Transcript of Sarcoma - Cancer Discovery · sarcoma cells to histone deacetylase (HDAC) inhibitors, the...
386 | CANCER DISCOVERY MAY 2012 www.aacrjournals.org
Major finding: ROR1 promotes EGF-induced, ERBB3-dependent PI3K pathway activation.
Clinical relevance: Gefitinib-resistant lung cancer cells are sensitive to ROR1 inhibition.
Impact: Targeting ROR1 may be an effective strategy for lung cancer treatment.
Lung Cancer
ROR1 MEDIATES EGFR SIGNALING IN LUNG ADENOCARCINOMA(EGFR) and led to activation of the PI3K pathway by pro-moting the activation of ERBB3 by EGFR and by phosphor-ylating SRC. These findings suggest that ROR1 sustains a favorable balance of prosurvival signaling and mediates the downstream effects of EGF signaling. Therefore, ROR1 may be an attractive therapeutic target in lung adenocarcinomas, which frequently harbor activating EGFR mutations and de-velop secondary resistance mutations following treatment with EGFR inhibitors such as gefitinib. ROR1 knockdown not only suppressed the growth of gefitinib-resistant, EGFR-mutant lung adenocarcinoma cells but also suppressed ge-fitinib-sensitive, EGFR wild-type cells, suggesting that lung adenocarcinoma cells are dependent on ROR1 for survival re-gardless of EGFR mutational status and that targeting ROR1 may be an effective therapeutic strategy for this disease. ≠
Yamaguchi T, Yanagisawa K, Sugiyama R, Hosono Y, Shimada Y, Arima C, et al. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell 2012;21:348–61.
Some cancers are dependent on aberrant activation of lineage-specific developmental regulators that drive prolif-eration of particular cell types. Lung adenocarcinomas have previously been shown to be dependent on NK2 homeobox 1 (NKX2-1), a homeodomain transcription factor that plays an essential role in lung development. Yamaguchi and col-leagues sought to characterize the downstream events of NKX2-1 activation by performing microarray analysis of a human peripheral lung epithelial cell line stably expressing NKX2-1 and identified receptor tyrosine kinase-like orphan recep-tor 1 (ROR1) as one of the most highly upregulated genes. Chromatin immunoprecipitation showed that ROR1 is a direct target of NKX2-1, and coexpression of NKX2-1 and ROR1 was observed in a panel of lung adenocarcinoma pa-tient samples. Knockdown of ROR1 inhibited lung adeno-carcinoma growth in vitro and suppressed xenograft tumor growth, indicating that induction of ROR1 by NKX2-1 is re-quired for tumor cell survival. The authors found that ROR1 repressed proapoptotic p38 signaling, and in response to epi-dermal growth factor (EGF), ROR1 bound to EGF receptor
these proteins together. ATF2 was required for recruiting SS18–SSX and TLE1 to cAMP-re-sponsive elements, which provides a potential explanation for how SS18–SSX might regulate transcription without being able to directly bind DNA. TLE1 was responsible for incor-porating EZH2 and HDAC1 into the SS18–SSX complex, which was associated with
increased histone H3 lysine-27 trimethylation and suppres-sion of ATF2 target gene expression. ATF2 target gene expres-sion could be restored by HDAC inhibition, which inhibited TLE1 recruitment to the SS18–SSX complex. Together, these findings suggest that SS18–SSX couples ATF2 and TLE1 ac-tivity to suppress ATF2 targets and provide a mechanistic rationale for the use of HDAC inhibitors in synovial sarcoma treatment. ≠
Su L, Sampaio AV, Jones KB, Pacheco M, Goytain A, Lin S, et al. Deconstruction of the SS18–SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell 2012;21:333–47.
Synovial sarcomas are aggressive soft-tissue tumors frequently occurring near joints that are characterized by a SS18–SSX fusion tran-script resulting from a reciprocal transloca-tion between chromosomes 18 and X. Because of its association with chromatin remodel-ing proteins and the sensitivity of synovial sarcoma cells to histone deacetylase (HDAC) inhibitors, the SS18–SSX oncoprotein is thought to drive epigenetically mediated transcriptional deregulation, but its mechanism of action has remained unknown. To gain insight into the role of SS18–SSX, Su and colleagues immunopre-cipitated SS18–SSX from synovial sarcoma cells and identi-fied interacting proteins via mass spectrometry. Two master transcriptional regulators, activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1) were identified as SS18–SSX interactors and were both required for synovial sarcoma cell growth and colony formation. ATF2 and TLE1 did not interact in the absence of SS18–SSX, sug-gesting that the fusion oncoprotein acts as a scaffold to bring
Major finding: SS18–SSX couples ATF2 DNA-binding activity to TLE1-mediated epigenetic repression.
Clinical relevance: HDAC inhibitors interfere with TLE1 recruitment and rescue ATF2 target gene expression.
Impact: These findings provide insight into the function of the SS18–SSX oncoprotein.
Sarcoma
SS18–SSX MEDIATES ATF2 TARGET GENE SUPPRESSION IN SYNOVIAL SARCOMA
reSeArCh wATCh
Cancer Research. on October 23, 2020. © 2012 American Association forcancerdiscovery.aacrjournals.org Downloaded from
Published OnlineFirst March 29, 2012; DOI: 10.1158/2159-8290.CD-RW2012-042
2012;2:386. Published OnlineFirst March 29, 2012.Cancer Discovery ROR1 Mediates EGFR Signaling in Lung Adenocarcinoma
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Cancer Research. on October 23, 2020. © 2012 American Association forcancerdiscovery.aacrjournals.org Downloaded from
Published OnlineFirst March 29, 2012; DOI: 10.1158/2159-8290.CD-RW2012-042
