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7. Supplemental Figure Legends from ATM Regulates 3-Methylpurine-DNA Glycosylase and Promotes Therapeutic Resistance to Alkylating Agents

Author

Agnihotri, Sameer, primary, Burrell, Kelly, primary, Buczkowicz, Pawel, primary, Remke, Marc, primary, Golbourn, Brian, primary, Chornenkyy, Yevgen, primary, Gajadhar, Aaron, primary, Fernandez, Nestor A., primary, Clarke, Ian D., primary, Barszczyk, Mark S., primary, Pajovic, Sanja, primary, Ternamian, Christian, primary, Head, Renee, primary, Sabha, Nesrin, primary, Sobol, Robert W., primary, Taylor, Michael D., primary, Rutka, James T., primary, Jones, Chris, primary, Dirks, Peter B., primary, Zadeh, Gelareh, primary, and Hawkins, Cynthia, primary

Published
2023
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8. Data from ATM Regulates 3-Methylpurine-DNA Glycosylase and Promotes Therapeutic Resistance to Alkylating Agents

Author

Agnihotri, Sameer, primary, Burrell, Kelly, primary, Buczkowicz, Pawel, primary, Remke, Marc, primary, Golbourn, Brian, primary, Chornenkyy, Yevgen, primary, Gajadhar, Aaron, primary, Fernandez, Nestor A., primary, Clarke, Ian D., primary, Barszczyk, Mark S., primary, Pajovic, Sanja, primary, Ternamian, Christian, primary, Head, Renee, primary, Sabha, Nesrin, primary, Sobol, Robert W., primary, Taylor, Michael D., primary, Rutka, James T., primary, Jones, Chris, primary, Dirks, Peter B., primary, Zadeh, Gelareh, primary, and Hawkins, Cynthia, primary

Published
2023
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9. Supplemental Figures 1 - 9 from ATM Regulates 3-Methylpurine-DNA Glycosylase and Promotes Therapeutic Resistance to Alkylating Agents

Author

Agnihotri, Sameer, primary, Burrell, Kelly, primary, Buczkowicz, Pawel, primary, Remke, Marc, primary, Golbourn, Brian, primary, Chornenkyy, Yevgen, primary, Gajadhar, Aaron, primary, Fernandez, Nestor A., primary, Clarke, Ian D., primary, Barszczyk, Mark S., primary, Pajovic, Sanja, primary, Ternamian, Christian, primary, Head, Renee, primary, Sabha, Nesrin, primary, Sobol, Robert W., primary, Taylor, Michael D., primary, Rutka, James T., primary, Jones, Chris, primary, Dirks, Peter B., primary, Zadeh, Gelareh, primary, and Hawkins, Cynthia, primary

Published
2023
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10. Supplemental Methods from ATM Regulates 3-Methylpurine-DNA Glycosylase and Promotes Therapeutic Resistance to Alkylating Agents

Author

Agnihotri, Sameer, primary, Burrell, Kelly, primary, Buczkowicz, Pawel, primary, Remke, Marc, primary, Golbourn, Brian, primary, Chornenkyy, Yevgen, primary, Gajadhar, Aaron, primary, Fernandez, Nestor A., primary, Clarke, Ian D., primary, Barszczyk, Mark S., primary, Pajovic, Sanja, primary, Ternamian, Christian, primary, Head, Renee, primary, Sabha, Nesrin, primary, Sobol, Robert W., primary, Taylor, Michael D., primary, Rutka, James T., primary, Jones, Chris, primary, Dirks, Peter B., primary, Zadeh, Gelareh, primary, and Hawkins, Cynthia, primary

Published
2023
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11. Supplemental Table 1 from ATM Regulates 3-Methylpurine-DNA Glycosylase and Promotes Therapeutic Resistance to Alkylating Agents

Author

Agnihotri, Sameer, primary, Burrell, Kelly, primary, Buczkowicz, Pawel, primary, Remke, Marc, primary, Golbourn, Brian, primary, Chornenkyy, Yevgen, primary, Gajadhar, Aaron, primary, Fernandez, Nestor A., primary, Clarke, Ian D., primary, Barszczyk, Mark S., primary, Pajovic, Sanja, primary, Ternamian, Christian, primary, Head, Renee, primary, Sabha, Nesrin, primary, Sobol, Robert W., primary, Taylor, Michael D., primary, Rutka, James T., primary, Jones, Chris, primary, Dirks, Peter B., primary, Zadeh, Gelareh, primary, and Hawkins, Cynthia, primary

Published
2023
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16. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies

Author

Rushlow, Diane E, Mol, Berber M, Kennett, Jennifer Y, Yee, Stephanie, Pajovic, Sanja, Thériault, Brigitte L, Prigoda-Lee, Nadia L, Spencer, Clarellen, Dimaras, Helen, Corson, Timothy W, Pang, Renée, Massey, Christine, Godbout, Roseline, Jiang, Zhe, Zacksenhaus, Eldad, Paton, Katherine, Moll, Annette C, Houdayer, Claude, Raizis, Anthony, Halliday, William, Lam, Wan L, Boutros, Paul C, Lohmann, Dietmar, Dorsman, Josephine C, and Gallie, Brenda L

Published
2013
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17. Splicing is an alternate oncogenic pathway activation mechanism in glioma

Author

Siddaway, Robert; https://orcid.org/0000-0003-2013-9467, Milos, Scott, Vadivel, Arun Kumaran Anguraj; https://orcid.org/0000-0002-6384-6316, Dobson, Tara H W, Swaminathan, Jyothishmathi, Ryall, Scott, Pajovic, Sanja, Patel, Palak G, Nazarian, Javad; https://orcid.org/0000-0002-1951-9828, Becher, Oren; https://orcid.org/0000-0003-4016-8492, Brudno, Michael; https://orcid.org/0000-0001-7947-2243, Ramani, Arun, Gopalakrishnan, Vidya; https://orcid.org/0000-0002-4448-4698, Hawkins, Cynthia; https://orcid.org/0000-0003-2618-4402, Siddaway, Robert; https://orcid.org/0000-0003-2013-9467, Milos, Scott, Vadivel, Arun Kumaran Anguraj; https://orcid.org/0000-0002-6384-6316, Dobson, Tara H W, Swaminathan, Jyothishmathi, Ryall, Scott, Pajovic, Sanja, Patel, Palak G, Nazarian, Javad; https://orcid.org/0000-0002-1951-9828, Becher, Oren; https://orcid.org/0000-0003-4016-8492, Brudno, Michael; https://orcid.org/0000-0001-7947-2243, Ramani, Arun, Gopalakrishnan, Vidya; https://orcid.org/0000-0002-4448-4698, and Hawkins, Cynthia; https://orcid.org/0000-0003-2618-4402

Abstract

High-grade diffuse glioma (HGG) is the leading cause of brain tumour death. While the genetic drivers of HGG have been well described, targeting these has thus far had little impact on survival suggesting other mechanisms are at play. Here we interrogate the alternative splicing landscape of pediatric and adult HGG through multi-omic analyses, uncovering an increased splicing burden compared with normal brain. The rate of recurrent alternative splicing in cancer drivers exceeds their mutation rate, a pattern that is recapitulated in pan-cancer analyses, and is associated with worse prognosis in HGG. We investigate potential oncogenicity by interrogating cancer pathways affected by alternative splicing in HGG; spliced cancer drivers include members of the RAS/MAPK pathway. RAS suppressor neurofibromin 1 is differentially spliced to a less active isoform in >80% of HGG downstream from REST upregulation, activating the RAS/MAPK pathway and reducing glioblastoma patient survival. Overall, our results identify non-mutagenic mechanisms by which cancers activate oncogenic pathways which need to accounted for in personalized medicine approaches.

Published
2022

18. Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells

Author

Barszczyk, Mark, Buczkowicz, Pawel, Castelo-Branco, Pedro, Mack, Stephen C., Ramaswamy, Vijay, Mangerel, Joshua, Agnihotri, Sameer, Remke, Marc, Golbourn, Brian, Pajovic, Sanja, Elizabeth, Cynthia, Yu, Man, Luu, Betty, Morrison, Andrew, Adamski, Jennifer, Nethery-Brokx, Kathleen, Li, Xiao-Nan, Van Meter, Timothy, Dirks, Peter B., Rutka, James T., Taylor, Michael D., Tabori, Uri, and Hawkins, Cynthia

Published
2014
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19. EPCO-16. ONCOHISTONE INTERACTOME PROFILING UNCOVERS MECHANISMS OF CHROMATIN DISRUPTION AND IDENTIFIES POTENTIAL THERAPEUTIC TARGETS IN PEDIATRIC HIGH-GRADE GLIOMA

Author

Siddaway, Robert, primary, Canty, Laura, additional, Pajovic, Sanja, additional, Coyaud, Etienne, additional, Milos, Scott, additional, Sbergio, Stefanie-Grace, additional, Lubanszky, Evan, additional, Yun, Haley, additional, Carette, Sheyenne, additional, Portante, Alessia, additional, Raught, Brian, additional, Campos, Eric, additional, and Hawkins, Cynthia, additional

Published
2021
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20. HGG-39. ALTERNATIVE SPLICING OF NEUROFIBROMIN 1 IS ASSOCIATED WITH ELEVATED MAPK ACTIVITY AND POOR PROGNOSIS IN HIGH-GRADE GLIOMA

Author

Siddaway, Robert, primary, Milos, Scott, additional, Vadivel, Arun, additional, Dobson, Tara, additional, Swaminathan, Jyothishmathi, additional, Ryall, Scott, additional, Pajovic, Sanja, additional, Nazarian, Javad, additional, Becher, Oren, additional, Brudno, Michael, additional, Ramani, Arun, additional, Gopalakrishnan, Vidya, additional, and Hawkins, Cynthia, additional

Published
2021
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21. Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Author

Ryall, Scott, Zapotocky, Michal, Fukuoka, Kohei, Nobre, Liana, Guerreiro Stucklin, Ana, Bennett, Julie, Siddaway, Robert, Li, Christopher, Pajovic, Sanja, Arnoldo, Anthony, Kowalski, Paul E, Johnson, Monique, Sheth, Javal, Lassaletta, Alvaro, Tatevossian, Ruth G, Orisme, Wilda, Qaddoumi, Ibrahim, Surrey, Lea F, Li, Marilyn M, Waanders, Angela J, Gilheeney, Stephen, Rosenblum, Marc, Bale, Tejus, Tsang, Derek S, Laperriere, Normand, Kulkarni, Abhaya, Ibrahim, George M, Drake, James, Dirks, Peter, Taylor, Michael D, et al, and University of Zurich

Subjects
1307 Cell Biology, 10036 Medical Clinic, 610 Medicine & health, 2730 Oncology, 1306 Cancer Research
Published
2020

24. Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

Author

Ryall, Scott, primary, Zapotocky, Michal, additional, Fukuoka, Kohei, additional, Nobre, Liana, additional, Guerreiro Stucklin, Ana, additional, Bennett, Julie, additional, Siddaway, Robert, additional, Li, Christopher, additional, Pajovic, Sanja, additional, Arnoldo, Anthony, additional, Kowalski, Paul E., additional, Johnson, Monique, additional, Sheth, Javal, additional, Lassaletta, Alvaro, additional, Tatevossian, Ruth G., additional, Orisme, Wilda, additional, Qaddoumi, Ibrahim, additional, Surrey, Lea F., additional, Li, Marilyn M., additional, Waanders, Angela J., additional, Gilheeney, Stephen, additional, Rosenblum, Marc, additional, Bale, Tejus, additional, Tsang, Derek S., additional, Laperriere, Normand, additional, Kulkarni, Abhaya, additional, Ibrahim, George M., additional, Drake, James, additional, Dirks, Peter, additional, Taylor, Michael D., additional, Rutka, James T., additional, Laughlin, Suzanne, additional, Shroff, Manohar, additional, Shago, Mary, additional, Hazrati, Lili-Naz, additional, D'Arcy, Colleen, additional, Ramaswamy, Vijay, additional, Bartels, Ute, additional, Huang, Annie, additional, Bouffet, Eric, additional, Karajannis, Matthias A., additional, Santi, Mariarita, additional, Ellison, David W., additional, Tabori, Uri, additional, and Hawkins, Cynthia, additional

Published
2020
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25. Regulation of p14ARF expression by miR-24: a potential mechanism compromising the p53 response during retinoblastoma development

Author

To Kwong-Him, Pajovic Sanja, Gallie Brenda L, and Thériault Brigitte L

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Most human cancers show inactivation of both pRB- and p53-pathways. While retinoblastomas are initiated by loss of the RB1 tumor suppressor gene, TP53 mutations have not been found. High expression of the p53-antagonist MDM2 in human retinoblastomas may compromise p53 tumor surveillance so that TP53 mutations are not selected for in retinoblastoma tumorigenesis. We previously showed that p14ARF protein, which activates p53 by inhibiting MDM2, is low in retinoblastomas despite high mRNA expression. Methods In human fetal retinas, adult retinas, and retinoblastoma cells, we determined endogenous p14ARF mRNA, ARF protein, and miR-24 expression, while integrity of p53 signalling in WERI-Rb1 cells was tested using an adenovirus vector expressing p14ARF. To study p14ARF biogenesis, retinoblastoma cells were treated with the proteasome inhibitor, MG132, and siRNA against miR-24. Results In human retinoblastoma cell lines, p14ARF mRNA was disproportionally high relative to the level of p14ARF protein expression, suggesting a perturbation of p14ARF regulation. When p14ARF was over-expressed by an adenovirus vector, expression of p53 and downstream targets increased and cell growth was inhibited indicating an intact p14ARF-p53 axis. To investigate the discrepancy between p14ARF mRNA and protein in retinoblastoma, we examined p14ARF biogenesis. The proteasome inhibitor, MG132, did not cause p14ARF accumulation, although p14ARF normally is degraded by proteasomes. miR-24, a microRNA that represses p14ARF expression, is expressed in retinoblastoma cell lines and correlates with lower protein expression when compared to other cell lines with high p14ARF mRNA. Transient over-expression of siRNA against miR-24 led to elevated p14ARF protein in retinoblastoma cells. Conclusions In retinoblastoma cells where high levels of p14ARF mRNA are not accompanied by high p14ARF protein, we found a correlation between miR-24 expression and low p14ARF protein. p14ARF protein levels were restored without change in mRNA abundance upon miR-24 inhibition suggesting that miR-24 could functionally repress expression, effectively blocking p53 tumor surveillance. During retinal tumorigenesis, miR-24 may intrinsically compromise the p53 response to RB1 loss.

Published
2012
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29. Additional file 8: Figure S4. of Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Author

Ryall, Scott, Krishnatry, Rahul, Arnoldo, Anthony, Buczkowicz, Pawel, Mistry, Matthew, Siddaway, Robert, Ling, Cino, Pajovic, Sanja, Yu, Man, Rubin, Joshua, Hukin, Juliette, Steinbok, Paul, Bartels, Ute, Bouffet, Eric, Tabori, Uri, and Hawkins, Cynthia

Subjects
endocrine system, technology, industry, and agriculture, complex mixtures, eye diseases
Abstract

Droplet digital PCR minimum mutant allele frequency detection. (PPTX 38Â kb)

Published
2016
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30. Additional file 6: Table S3. of Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Author

Ryall, Scott, Krishnatry, Rahul, Arnoldo, Anthony, Buczkowicz, Pawel, Mistry, Matthew, Siddaway, Robert, Ling, Cino, Pajovic, Sanja, Yu, Man, Rubin, Joshua, Hukin, Juliette, Steinbok, Paul, Bartels, Ute, Bouffet, Eric, Tabori, Uri, and Hawkins, Cynthia

Abstract

Droplet digital PCR H3K27M detection validation as compared to WES and Sanger Sequencing. (DOCX 12Â kb)

Published
2016
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31. Additional file 4: Figure S2. of Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Author

Ryall, Scott, Krishnatry, Rahul, Arnoldo, Anthony, Buczkowicz, Pawel, Mistry, Matthew, Siddaway, Robert, Ling, Cino, Pajovic, Sanja, Yu, Man, Rubin, Joshua, Hukin, Juliette, Steinbok, Paul, Bartels, Ute, Bouffet, Eric, Tabori, Uri, and Hawkins, Cynthia

Abstract

Droplet digital PCR annealing temperature comparison. (PPTX 173Â kb)

Published
2016
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32. Additional file 12: Figure S5. of Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Author

Ryall, Scott, Krishnatry, Rahul, Arnoldo, Anthony, Buczkowicz, Pawel, Mistry, Matthew, Siddaway, Robert, Ling, Cino, Pajovic, Sanja, Yu, Man, Rubin, Joshua, Hukin, Juliette, Steinbok, Paul, Bartels, Ute, Bouffet, Eric, Tabori, Uri, and Hawkins, Cynthia

Abstract

Clinical characteristics of H3K27M and H3WT paediatric thalamic glioma Canadian cohort. (PPTX 84Â kb)

Published
2016
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33. Additional file 10: Table S6. of Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Author

Ryall, Scott, Krishnatry, Rahul, Arnoldo, Anthony, Buczkowicz, Pawel, Mistry, Matthew, Siddaway, Robert, Ling, Cino, Pajovic, Sanja, Yu, Man, Rubin, Joshua, Hukin, Juliette, Steinbok, Paul, Bartels, Ute, Bouffet, Eric, Tabori, Uri, and Hawkins, Cynthia

Subjects
neoplasms, nervous system diseases
Abstract

Clinical characteristics of paediatric thalamic glioma Canadian cohort. (DOCX 12Â kb)

Published
2016
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34. Additional file 3: Figure S1. of Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Author

Ryall, Scott, Krishnatry, Rahul, Arnoldo, Anthony, Buczkowicz, Pawel, Mistry, Matthew, Siddaway, Robert, Ling, Cino, Pajovic, Sanja, Yu, Man, Rubin, Joshua, Hukin, Juliette, Steinbok, Paul, Bartels, Ute, Bouffet, Eric, Tabori, Uri, and Hawkins, Cynthia

Subjects
endocrine system, technology, industry, and agriculture, complex mixtures, eye diseases
Abstract

Droplet digital PCR minimum concentration detection. (PPTX 55Â kb)

Published
2016
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35. Additional file 5: Figure S3. of Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Author

Ryall, Scott, Krishnatry, Rahul, Arnoldo, Anthony, Buczkowicz, Pawel, Mistry, Matthew, Siddaway, Robert, Ling, Cino, Pajovic, Sanja, Yu, Man, Rubin, Joshua, Hukin, Juliette, Steinbok, Paul, Bartels, Ute, Bouffet, Eric, Tabori, Uri, and Hawkins, Cynthia

Subjects
eye diseases
Abstract

Droplet digital PCR pre-PCR digestion versus no digestion comparison. (PPTX 102Â kb)

Published
2016
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36. Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Author

Ryall, Scott, primary, Krishnatry, Rahul, additional, Arnoldo, Anthony, additional, Buczkowicz, Pawel, additional, Mistry, Matthew, additional, Siddaway, Robert, additional, Ling, Cino, additional, Pajovic, Sanja, additional, Yu, Man, additional, Rubin, Joshua B., additional, Hukin, Juliette, additional, Steinbok, Paul, additional, Bartels, Ute, additional, Bouffet, Eric, additional, Tabori, Uri, additional, and Hawkins, Cynthia, additional

Published
2016
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38. ATM Regulates 3-Methylpurine-DNA Glycosylase and Promotes Therapeutic Resistance to Alkylating Agents

Author

Agnihotri, Sameer, primary, Burrell, Kelly, additional, Buczkowicz, Pawel, additional, Remke, Marc, additional, Golbourn, Brian, additional, Chornenkyy, Yevgen, additional, Gajadhar, Aaron, additional, Fernandez, Nestor A., additional, Clarke, Ian D., additional, Barszczyk, Mark S., additional, Pajovic, Sanja, additional, Ternamian, Christian, additional, Head, Renee, additional, Sabha, Nesrin, additional, Sobol, Robert W., additional, Taylor, Michael D., additional, Rutka, James T., additional, Jones, Chris, additional, Dirks, Peter B., additional, Zadeh, Gelareh, additional, and Hawkins, Cynthia, additional

Published
2014
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39. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

Author

Buczkowicz, Pawel, primary, Hoeman, Christine, additional, Rakopoulos, Patricia, additional, Pajovic, Sanja, additional, Letourneau, Louis, additional, Dzamba, Misko, additional, Morrison, Andrew, additional, Lewis, Peter, additional, Bouffet, Eric, additional, Bartels, Ute, additional, Zuccaro, Jennifer, additional, Agnihotri, Sameer, additional, Ryall, Scott, additional, Barszczyk, Mark, additional, Chornenkyy, Yevgen, additional, Bourgey, Mathieu, additional, Bourque, Guillaume, additional, Montpetit, Alexandre, additional, Cordero, Francisco, additional, Castelo-Branco, Pedro, additional, Mangerel, Joshua, additional, Tabori, Uri, additional, Ho, King Ching, additional, Huang, Annie, additional, Taylor, Kathryn R, additional, Mackay, Alan, additional, Bendel, Anne E, additional, Nazarian, Javad, additional, Fangusaro, Jason R, additional, Karajannis, Matthias A, additional, Zagzag, David, additional, Foreman, Nicholas K, additional, Donson, Andrew, additional, Hegert, Julia V, additional, Smith, Amy, additional, Chan, Jennifer, additional, Lafay-Cousin, Lucy, additional, Dunn, Sandra, additional, Hukin, Juliette, additional, Dunham, Chris, additional, Scheinemann, Katrin, additional, Michaud, Jean, additional, Zelcer, Shayna, additional, Ramsay, David, additional, Cain, Jason, additional, Brennan, Cameron, additional, Souweidane, Mark M, additional, Jones, Chris, additional, Allis, C David, additional, Brudno, Michael, additional, Becher, Oren, additional, and Hawkins, Cynthia, additional

Published
2014
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43. The TAg-RB Murine Retinoblastoma Cell of Origin Has Immunohistochemical Features of Differentiated Müller Glia with Progenitor Properties

Author

Pajovic, Sanja, primary, Corson, Timothy W., additional, Spencer, Clarellen, additional, Dimaras, Helen, additional, Orlic-Milacic, Marija, additional, Marchong, Mellone N., additional, To, Kwong-Him, additional, Thériault, Brigitte, additional, Auspitz, Mark, additional, and Gallie, Brenda L., additional

Published
2011
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46. Retinoblastoma: The Evidence Does Matter

Author

Prigoda-Leea, Nadia L., primary, Rushlowa, Diane, additional, Piovesan, Beata, additional, Zhang, Katherine, additional, Dimaras, Helen, additional, Pajovic, Sanja, additional, and Galliea, Brenda L., additional

Published
2009
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49. Transcriptional and Epigenetic Regulation of KIF14 Overexpression in Ovarian Cancer.

Author

Thériault, Brigitte L., Basavarajappa, Halesha D., Lim, Harvey, Pajovic, Sanja, Gallie, Brenda L., and Corson, Timothy W.

Subjects
OVARIAN cancer, KINESIN, GENE expression, HEALTH outcome assessment, CELL adhesion, CANCER cells, ONCOGENES, GENETIC transcription, EPIGENETICS
Abstract

KIF14 (kinesin family member 14) is a mitotic kinesin and an important oncogene in several cancers. Tumor KIF14 expression levels are independently predictive of poor outcome, and in cancer cells KIF14 can modulate metastatic behavior by maintaining appropriate levels of cell adhesion and migration proteins at the cell membrane. Thus KIF14 is an exciting potential therapeutic target. Understanding KIF14's regulation in cancer cells is crucial to the development of effective and selective therapies to block its tumorigenic function(s). We previously determined that close to 30% of serous ovarian cancers (OvCa tumors) exhibit low-level genomic gain, indicating one mechanism of KIF14 overexpression in tumors. We now report on transcriptional and epigenetic regulation of KIF14. Through promoter deletion analyses, we identified one cis-regulatory region containing binding sites for Sp1, HSF1 and YY1. siRNA-mediated knockdown of these transcription factors demonstrated endogenous regulation of KIF14 overexpression by Sp1 and YY1, but not HSF1. ChIP experiments confirmed an enrichment of both Sp1 and YY1 binding to the endogenous KIF14 promoter in OvCa cell lines with high KIF14 expression. A strong correlation was seen in primary serous OvCa tumors between Sp1, YY1 and KIF14 expression, further evidence that these transcription factors are important players in KIF14 overexpression. Hypomethylation patterns were observed in primary serous OvCa tumors, suggesting a minor role for promoter methylation in the control of KIF14 gene expression. miRNA expression analysis determined that miR-93, miR-144 and miR-382 had significantly lower levels of expression in primary serous OvCa tumors than normal tissues; treatment of an OvCa cell line with miRNA mimics and inhibitors specifically modulated KIF14 mRNA levels, pointing to potential novel mechanisms of KIF14 overexpression in primary tumors. Our findings reveal multiple mechanisms of KIF14 upregulation in cancer cells, offering new targets for therapeutic interventions to reduce KIF14 in tumors, aiming at improved prognosis. [ABSTRACT FROM AUTHOR]

Published
2014
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50. The in vivoInteraction Landscape of Histones H3.1 and H3.3

Author

Siddaway, Robert, Milos, Scott, Coyaud, Étienne, Yun, Hwa Young, Morcos, Shahir M., Pajovic, Sanja, Campos, Eric I., Raught, Brian, and Hawkins, Cynthia

Abstract

Chromatin structure, transcription, DNA replication, and repair are regulated vialocus-specific incorporation of histone variants and posttranslational modifications that guide effector chromatin-binding proteins. Here we report unbiased, quantitative interactomes for the replication-coupled (H3.1) and replication-independent (H3.3) histone H3 variants based on BioID proximity labeling, which allows interactions in intact, living cells to be detected. Along with a significant proportion of previously reported interactions detected by affinity purification followed by mass spectrometry, three quarters of the 608 histone-associated proteins that we identified are new, uncharacterized histone associations. The data reveal important biological nuances not captured by traditional biochemical means. For example, we found that the chromatin assembly factor-1 histone chaperone not only deposits the replication-coupled H3.1 histone variant during S-phase but also associates with H3.3 throughout the cell cycle in vivo. We also identified other variant-specific associations, such as with transcription factors, chromatin regulators, and with the mitotic machinery. Our proximity-based analysis is thus a rich resource that extends the H3 interactome and reveals new sets of variant-specific associations.

Published
2022
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