Molecular and Cellular Biology / Genetics最新文献

{"title":"Abstract 1942: Quantitative D2O proteomics reveals ATG9A-dependent autophagy substrates that are degraded independently of the LC3-lipidation machinery","authors":"Colten M. McEwan, David G. Broadbent, Ashari R Kannangara, Daniel M. Poole, Bradley C. Naylor, J. C. Price, Jens C. Schmidt, J. Andersen","doi":"10.1158/1538-7445.AM2021-1942","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1942","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87901473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2335: Targeting MYC-enhanced glycolysis in small cell lung cancer","authors":"K. Cargill, C. Stewart, E. Park, R. Cardnell, Youhong Fan, Qi Wang, L. Diao, W. Chan, P. Lorenzi, Jing Wang, L. Byers","doi":"10.1158/1538-7445.AM2021-2335","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2335","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88223942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2225: Transposable elements are an abundant and pan-cancer source of shared tumor-specific antigens and membrane targets","authors":"Nakul M. Shah, H. S. Jang, J. H. Maeng, S. Tzeng, A. Wu, Changxu Fan, Noah L Basri, B. Katz, Daofeng Li, X. Xing, B. Evans, Ting Wang","doi":"10.1158/1538-7445.AM2021-2225","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2225","url":null,"abstract":"Transposable elements (TEs) represent close to half of the genome and are generally disregarded in genomic studies due to their silencing in somatic tissues and difficulty in mapping to their repetitive sequences. Recent studies have revealed that epigenetic dysregulation in cancer can unlock the regulatory potential of transposable elements (TEs), and they can play an important role in cancer progression and oncogenesis. One important consequence of this phenomenon is the pervasive activation of TEs9 intrinsic promoters, which leads to generation of thousands of unique transcripts. Many of these transcripts splice into downstream genes and lead to the generation of TE-gene chimeric transcripts. These transcripts can alter the main reading frame of the original transcript to generate unique isoforms of the target gene or generate novel out-of-frame peptides that could be therapeutic targets. In this study, we analyzed the transcriptomes of 11,092 samples from 33 TCGA cancer types and 675 cancer cell lines to comprehensively profile all TE-gene fusion transcripts. Using somatic tissues from FANTOM5 and GTEx, we filtered these transcripts for tumor-specificity and discovered 2,642 tumor-specific TE-gene transcripts that promiscuously occur in nearly all TCGA tumor samples. Computational prediction of reading frames of these transcripts identified 1,202 candidates with the potential to generate tumor-specific TE-derived antigens (TS-TEAs). We further analyzed tumor mass spectrometry data from breast adenocarcinoma and ovarian cancer and confirmed that unique peptide sequences from TS-TEAs could be detected. In addition, we performed HLA-pulldown mass spectrometry and confirmed that TS-TEAs are presented on the cell surface in cancer cell lines. Given that these antigens are highly shared within and across cancer types, we assessed their potential to generate universal antigen-based therapies. Optimal combinations of 5, 10, and 20 TS-TEAs could generate unique peptides that bind to patient-specific HLA alleles for 39.2%, 50.8%, and 60.8% of all TCGA tumors respectively. Lastly, we highlight the tumor-specific membrane proteins transcribed from TE-exapted promoters that can potentially expose novel epitopes on the extracellular surface of cancer cells. These can be valuable targets of CAR-T or alternative antibody-based therapies. In conclusion, we showcase the high prevalence of TE-derived promoter activation in cancer and suggest multiple avenues by which this phenomenon can be targeted therapeutically. Citation Format: Nakul M. Shah, Hyo Sik Jang, Ju Heon Maeng, Shin-Cheng Tzeng, Angela Wu, Changxu Fan, Noah L. Basri, Benjamin Katz, Daofeng Li, Xiaoyun Xing, Bradley S. Evans, Ting Wang. Transposable elements are an abundant and pan-cancer source of shared tumor-specific antigens and membrane targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR;","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86495932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2370: Tumor suppression potential of tRNA modification enzyme TruBs via let-7","authors":"R. Kurimoto, Hiroki Tsutsumi, Sakiko Ikeuchi, H. Asahara","doi":"10.1158/1538-7445.AM2021-2370","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2370","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82703609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2312: Identification of tumor associated genes using transcriptome analysis","authors":"Guoqiang Liang, Jinqiu Sun, Yiwei Liu, Dongxue Liu, Shengxian Liang, Rui Guo, L. Zhong","doi":"10.1158/1538-7445.AM2021-2312","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2312","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82718800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 86: O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation","authors":"Lorela Ciraku, Zachary A. Bacigalupa, Rebecca A. Moeller, Jing Ju, Rusia Lee, C. Ferrer, S. Trefely, N. Snyder, L. D'agostino, C. Katsetos, Wenyin Shi, M. Reginato","doi":"10.1158/1538-7445.AM2021-86","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-86","url":null,"abstract":"Cancer cells alter their metabolism to increase cell growth. A subset of the glucose taken up is shunted into the hexosamine biosynthetic pathway where it is used to synthesize UDP-GlcNAc, a substrate of O-GlcNAc transferase (OGT), which modifies cytoplasmic and nuclear proteins with O-linked sugar moieties. Here, we show that OGT and O-GlcNAcylation are elevated in glioblastoma (GBM) cancer cells and in GBM patient samples that correlates with disease progression. Reduction of OGT expression in GBM cells led to significant reduction in anchorage-independent growth, acetyl-CoA levels, and decrease in free fatty acids. Conversely, overexpressing OGT in GBM cells had the opposite effect. Reducing OGT expression in GBMcells transplanted in an orthotopic intracranial mouse model reduced tumor growth and extended survival. Mechanistically, we show that OGT overexpression increases carbon-flux of acetate to acetyl-CoA, a reaction carried by the enzyme acetyl-CoA synthetase 2 (ACSS2). Indeed, OGT regulates ACSS2 protein levels and O-GlcNAcylation increases ACSS2phosphorylation on Ser-267 in a cyclin dependent kinase 5 (CDK5)-dependent manner, which regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Using an ex vivo GBM brain slice model we show that treatment of GBM-transplanted slices with OGT inhibitor Ac-GlcNAc-5S or pan-cdk inhibitor dinaciclib reduced growth of pre-formed tumors in cultured brain slices. These results suggest a crucial role for O-GlcNAc signaling in transducing nutritional state to regulate acetate metabolism and identify OGT and CDK5 as novel therapeutic targets for treatment of glioblastoma. Citation Format: Lorela Ciraku, Zachary Bacigalupa, Rebecca Moeller, Jing Ju, Rusia H. Lee, Christina Ferrer, Sophie Trefely, Nathaniel W. Snyder, Luca D'Agostino, Christos D. Katsetos, Wenyin Shi, Mauricio J. Reginato. O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 86.","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82817227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2001: Krupple like factor 10 modulates stem cell phenotype of pancreatic adenocarcinoma via transcriptional regulation of Notch signal pathway","authors":"Y. Tsai, Su-Liang Chen, S. Peng, Kuang-Hung Cheng, S. Jiang, S. Chuang, Chang Hui-ju","doi":"10.1158/1538-7445.AM2021-2001","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2001","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86750700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2240: Genomic profiling of smoldering multiple myeloma classifies distinct molecular groups","authors":"Shankara K. Anand, M. Bustoros, F. Aguet, R. Sklavenitis-Pistofidis, R. Redd, Binyamin Zhitomirsky, Andrew J. Dunford, Y. Tai, S. Chavda, Cody J Boehner, C. Neuse, T. Casneuf, L. Trippa, C. Stewart, K. Yong, I. Ghobrial, G. Getz","doi":"10.1158/1538-7445.AM2021-2240","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2240","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"85 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91463228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 2042: A cytoskeletal function for PBRM1: reading methylated microtubules to maintain genomic stability","authors":"Menuka Karki, Rahul K. Jangid, R. Anish, Riyad N. H. Seervai, Jean-Philippe Bertocchio, Takashi Hotta, P. Msaouel, S. Jung, S. Grimm, C. Coarfa, B. Weissman, R. Ohi, K. Verhey, Courtney Hodges, R. Dere, I. Park, B. Prasad, W. K. Rathmell, Cheryl Walker, D. Tripathi","doi":"10.1158/1538-7445.AM2021-2042","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2042","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88939480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB186: MAPK pathway activation represents a therapeutic vulnerability inASCL1-driven SCLC","authors":"Rebecca Caeser, Christopher H. Hulton, Vidushi Durani, Emily A. Costa, M. Little, Nisargbhai S. Shah, E. Stanchina, J. Poirier, C. Rudin, T. Sen","doi":"10.1158/1538-7445.AM2021-LB186","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB186","url":null,"abstract":"Background Lung cancer is the leading cause of cancer death, killing more people than colon, breast, and prostate cancers combined (Siegel et al. 2013). Small cell lung cancer (SCLC) is a high grade neuroendocrine tumor accounting for ~15% of all lung cancers (Hann et al. 2019). Metastasis is often found at first diagnosis, making SCLC exceptionally lethal (2-year survival l Gao et al. 2013; Wagle et al. 2018). This striking difference is not well understood and previous attempts to determine whether this might be therapeutically important (Ravi et al, 1998; Cristea et al. 2020) have had conflicting conclusions. SCLC has recently been defined by the relative expression of four major transcriptional regulators (ASCL1, NeuroD1, POU2F3, YAP1) (Rudin et al., 2019). In this study we aimed to elucidate the effect of MAPK activation in these different SCLC subtypes and explore its therapeutic vulnerability. Results We used a doxycycline-inducible vector for expression of MEKDDS217D/S221D (MEK1) in a cohort of ASCL1-, NEUROD1, and POU2F3- driven cell lines. Activation through MEK1 in ASCL1-driven SCLC cell lines resulted in a significant decrease in cell growth over 9 days. This was associated with a decrease in neuroendocrine markers ASCL1 and INSM1, a G2 cell cycle arrest and no significant increase in apoptotic cells. Expression of MEK1 in other SCLC subtypes and NSCLC failed to show any appreciable changes in cell growth. Remarkably, athymic mice injected with a MEK1 expressing ASCL1-driven cell line showed significantly slower tumor formation and longer survival than the ASCL1-driven cell line not expressing MEK1. Previous work established that hyperactivation of BRAFV600E, RAS and MYC can result in oncogene-induced senescence (Serrano et al. 1997) which is caused by upregulation of negative feedback such as SPRY2, DUSP6, ETV5 rather than MAPK pathway activation in some solid tumors and pre-B ALL (Courtois-Cox et al 2006; Shojaee et al. 2015). Similarly, we also observed strong upregulation of DUSP6, SPRY2, but not ETV5 upon MAPK activation. This was especially prominent in ASCL1-driven cell lines that changed from the normal phenotype of being in suspension to a more adherent morphology as a result of MAPK activation. Interestingly, phosphokinase array in the major subtype cell lines after MEK1 activation, demonstrated that, almost exclusively, the STAT pathways, in particular STAT3 through phosphorylation at S727 was strongly upregulated in the ASCL1-driven subtype. This prompted us to examine whether these cells were sensitive to STAT3 inhibition. Upon treatment with a STAT3 inhibitor, Stattic (1μM), ASCL1-driven SCLC cells reached their IC50 after 3-5 days in comparison to 9 days for other SCLC subtypes. NSCLC cells were resistant to STAT3 inhibition. Summary These findings suggest that ASCL1-driven SCLC in vitro and in vivo is sensitive to activation of MAPK signaling in comparison to other SCLC subtypes. Whilst activation of the MAPK pathway m","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"47 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91420345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}