RECENTLY PUBLISHED WORK

2020/09/2020

TUMOR SUPPRESSOR P53: FROM ENGAGING DNA TO TARGET GENE REGULATION

The p53 transcription factor confers its potent tumor suppressor functions primarily through the regulation of a large network of target genes. The recent explosion of next generation sequencing protocols has enabled the study of the p53 gene regulatory network (GRN) and underlying mechanisms at an unprecedented depth and scale, helping us to understand precisely how p53 controls gene regulation. Here, we discuss our current understanding of where and how p53 binds to DNA and chromatin, its pioneer-like role, and how this affects gene regulation. We provide an overview of the p53 GRN and the direct and indirect mechanisms through which p53 affects gene regulation. In particular, we focus on delineating the ubiquitous and cell type-specific network of regulatory elements that p53 engages; reviewing our understanding of how, where, and when p53 binds to DNA and the mechanisms through which these events regulate transcription. Finally, we discuss the evolution of the p53 GRN and how recent work has revealed remarkable differences between vertebrates, which are of particular importance to cancer researchers using mouse models.

2020/07/28

DOI: 10.1073/pnas.2001520117

THE PSEUDO-CASPASE FLIP(L) REGULATES CELL FATE FOLLOWING P53 ACTIVATION

p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.

ALL PUBLICATIONS

Since 2005

2020

The pseudo-caspase FLIP(L) regulates cell fate following p53 activation.

Lees A., McIntyre A. J., Crawford N. T., Falcone F., McCann C., Holohan C., Quinn G. P., Roberts J. Z., Sessler T., Gallagher P. F., Gregg G. M. A., McAllister K., McLaughling K. M., Allen W. L., Egan L.J., Ryan A. E., Labonte-Wilson M., Dunne P.D., Wappett M., Coyle V.M., Johnston P.G., Kerr E.M., Longley D. B., McDade S. S. Jul 28 2020;117(30):17808-17819 In: PNAS

Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer

Haughey, C. M., Mukherjee, D., Steele, R. E., Popple, A., Dura-Perez, L., Pickard, A., Patel, M., Jain, S., Mullan, P. B., Williams, R., Oliveira, P., Buckley, N. E., Honeychurch, J., S McDade, S., Illidge, T., Mills, I. G. & Eddie, S. L.,

29 Sep 2020, In : Cancers. 12, 10

Tumor suppressor p53: from engaging DNA to target gene regulation

Sammons, M. A., Nguyen, T. A. T., McDade, S. S. & Fischer, M.,

18 Sep 2020, In : Nucleic Acids Research. 48, 16, p. 8848-8869

Chronic loss of STAG2 leads to altered chromatin structure contributiong to de-regulated transcription in AML

Smith, J., Lappin, K., Craig, S., Liberante, F., McDade, S., Thompson, A., Mills, K. & Savage, K., 03 Sep 2020, In : JOURNAL OF TRANSLATIONAL MEDICINE. 18, p. 339-357 18 p.

Pevonedistat (MLN4924): mechanism of cell death induction and therapeutic potential in colorectal cancer

Ferris, J., Espona-Fiedler, M., Hamilton, C., Holohan, C., Crawford, N., McIntyre, A. J., Roberts, J. Z., Wappett, M., McDade, S. S., Longley, D. B. & Coyle, V., 21 Jul 2020, In : Cell death discovery. 6, 1, 61.

The SCFSkp2 ubiquitin ligase complex modulates TRAIL-R2-induced apoptosis by regulating FLIP(L)

Roberts, J. Z., Holohan, C., Sessler, T., Fox, J., Crawford, N., Riley, J. S., Khawaja, H., Majkut, J., Evergren, E., Humphreys, L. M., Ferris, J., Higgins, C., Espona-Fiedler, M., Moynagh, P., McDade, S. S. & Longley, D. B., 20 Apr 2020, In : Cell Death and Differentiation.

A revised model of TRAIL-R2 DISC assembly explains how FLIP(L) can inhibit or promote apoptosis

Humphreys, L. M., Fox, J. P., Higgins, C. A., Majkut, J., Sessler, T., McLaughlin, K., McCann, C., Roberts, J. Z., Crawford, N. T., McDade, S. S., Scott, C. J., Harrison, T. & Longley, D. B., 31 Jan 2020, In : EMBO Reports. e49254

Comparison of molecular assays for HPV testing in oropharyngeal squamous cell carcinomas: a population-based study in Northern Ireland

Craig, S., Anderson, L., Moran, M., Graham, L., Currie, K., Rooney, K., Robinson, M., Bingham, V., Cuschieri, K., McQuaid, S., Schache, A., Jones, T., McCance, D., Salto-Tellez, M., McDade, S. & James, J., Jan 2020, In : Cancer Epidemiology, Biomarkers, & Prevention. 29, 1, p. 31-38

Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

Haughey, C. M., Mukherjee, D., Steele, R. E., Popple, A., Dura-Perez, L., Pickard, A., Jain, S., Mullan, P. B., Williams, R., Oliveira, P., Buckley, N. E., Honeychurch, J., Williams, R., McDade, S., Illidge, T., Mills, I. G. & Eddie, S. L., 2020

2019

Recommendations for determining HPV status in patients with oropharyngeal cancers under TNM8 guidelines: a two-tier approach

Craig, S., Anderson, L., Schache, A., Moran, M., Graham, L., Currie, K., Rooney, K., Robinson, M., Upile, N., Brooker, R., Mesri, M., Bingham, V., McQuaid, S., Jones, T., McCance, D., Salto-Tellez, M., McDade, S. & James, J., 20 Mar 2019, In : British Journal of Cancer.

A Workbench using Evolutionary Genetic Algorithms for analyzing association in TCGA Data

Gilmore, A., Alderdice, M., Savage, K., O’Reilly, P. G., Roddy, A., Dunne, P., Lawler, M., McDade, S., Waugh, D. & McArt, D., 13 Feb 2019, In : Cancer Research.

2018

Cytoplasmic FLIP(S) and nuclear FLIP(L) mediate resistance of castrate-resistant prostate cancer to apoptosis induced by IAP antagonists

McCann, C., Crawford, N., Majkut, J., Holohan, C., Armstrong, C., Maxwell, P., Ong, C. W., LaBonte Wilson, M., McDade, S., Waugh, D. & Longley, D., 22 Oct 2018, In : Cell, Death & Disease. 9, 1081, 13 p., 1081.

Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy

Allen, W., Dunne, P., McDade, S., Scanlon, E., Loughrey, M., Coleman, H., McCann, C., McLaughlin, K., Nemeth, Z., Syed, N. A., Jithesh, P. V., Arthur, K., Wilson, R., Coyle, V., McArt, D., Johnston, P., Murray, G. I., Samuel, L. M., Nuciforo, P., Jimenez, J., Argiles, G., Dienstmann, R., Picariello, L., Nobili, S., Mini, E., Sheahan, K., Ryan, E., Tabernero, J., Messerini, L., Van Schaeybroeck, S., Lawler, M. & Longley, D., 13 Jun 2018, In : JCO Precision Oncology. 2018, p. 1-15

ΔNp63γ/SRC/Slug signalling axis promotes epithelial-to-mesenchymal transition in squamous cancers

Srivastava, K., Pickard, A., Craig, S., Quinn, G., Lambe, S., James, J., McCance, D. & McDade, S., 08 May 2018, In : Clinical Cancer Research. 24, 16, p. 3917-3927 11 p.

Encyclopedia of Cancer: Chapter TP53

McDade, S. & Fischer, M., 26 Jan 2018, . 3rd ed. Elsevier, Vol. 1. p. 483-495 13

2017

Transcription factor activities enhance markers of drug sensitivity in cancer

Garcia-Alonso, L. M., Iorio, F., Matchan, A., Fonseca, N. A., Jaaks, P., Peat, G., Pignatelli, M., Falcone, F., Benes, C. H., Dunham, I., Bignell, G. R., McDade, S., Garnett, M. J. & Saez-Rodriguez, J., 11 Dec 2017, In : Cancer Research. p. 1-35

Validation of a Metastatic Assay using biopsies to improve risk stratification in patients with prostate cancer treated with radical radiation therapy

Jain, S., Lyons, C. A., Walker, S. M., McQuaid, S., Hynes, S., Mitchell, D., Pang, B., Logan, G. E., McCavigan, A. M., O'Rourke, D., McArt, D., McDade, S., Mills, I., Prise, K. M., Knight, L. A., Steele, C. J., Medlow, P. W., Berge, V., Katz, B., Loblaw, D. A., Harkin, D. P., James, J., O'Sullivan, J. M., Kennedy, R. D. & Waugh, D. J., 10 Oct 2017, In : Annals of Oncology.

Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification

Dunne, P. D., Alderdice, M., O'Reilly, P. G., Roddy, A. C., McCorry, A. M. B., Richman, S., Maughan, T., McDade, S. S., Johnston, P. G., Longley, D. B., Kay, E., McArt, D. G. & Lawler, M., 31 May 2017, In : Nature Communications. 8, p. 15657 15657.

Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology

Walker, S. M., Knight, L. A., McCavigan, A. M., Logan, G. E., Berge, V., Sherif, A., Pandha, H., Warren, A. Y., Davidson, C., Uprichard, A., Blayney, J. K., Price, B., Jellema, G. L., Steele, C. J., Svindland, A., McDade, S. S., Eden, C. G., Foster, C., Mills, I. G., Neal, D. E., Mason, M. D., W Kay, E., Waugh, D. J., Harkin, D. P., Watson, R. W., Clarke, N. W. & Kennedy, R. D., 10 Apr 2017, In : European Urology.

p63 drives invasion in keratinocytes expressing HPV16 E6/E7 genes through regulation of Src-FAK signalling

Srivastava, K., Pickard, A., McDade, S. & McCance, D. J., 2017, In : Oncotarget. 8, 10, p. 16202-16219

2016

Challenging the cancer molecular stratification dogma: Intratumoral heterogeneity undermines consensus molecular subtypes and potential diagnostic value in colorectal cancer

Dunne, P. D., McArt, D. G., Bradley, C. A., O'Reilly, P. G., Barrett, H. L., Cummins, R., O'Grady, A., Arthur, K., Loughrey, M. B., Moore, W. L., McDade, S. S., Waugh, D. J., Hamilton, P. W., Longley, D. B., Kay, E. W., Johnston, P. G., Lawler, M., Salto-Tellez, M. & Van Schaeybroeck, S., 15 Aug 2016, In : Clinical Cancer Research.

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

Miller, R. E., Brough, R., Bajrami, I., Williamson, C. T., McDade, S., Campbell, J., Kigozi, A., Rafiq, R., Pemberton, H., Natrajan, R., Joel, J., Astley, H., Mahoney, C., Moore, J. D., Torrance, C., Gordan, J. D., Webber, J. T., Levin, R. S., Shokat, K. M., Bandyopadhyay, S., Lord, C. J. & Ashworth, A., 01 Jul 2016, In : Molecular Cancer Therapeutics. 15, 7, p. 1472-1484 13 p.

Identification of potentially pathogenic variants in candidate breast and ovarian cancer susceptibility genes in BRCAX patients

Savage, A. L., Chenevix-Trench, G., Jun Li, J., McDade, S. S., Morrison, P. J., McIntosh, S. A., Harkin, D. P. & Savage, K. I., Jun 2016, In : Current Oncology. 23, 3, p. e308 1 p., P089.

Immune-derived PD-L1 gene expression defines a subgroup of stage II/III colorectal cancer patients with favorable prognosis that may be harmed by adjuvant chemotherapy

Dunne, P. D., McArt, D. G., O'Reilly, P. G., Coleman, H. G., Allen, W. L., Loughrey, M., Van Schaeybroeck, S., McDade, S., Salto-Tellez, M., Longley, D. B., Lawler, M. & Johnston, P. G., 13 May 2016, In : Cancer Immunology Research.

2015

A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence

Brien, G. L., Healy, E., Jerman, E., Conway, E., Fadda, E., O'Donovan, D., Krivtsov, A. V., Rice, A. M., Kearney, C. J., Flaus, A., McDade, S. S., Martin, S. J., McLysaght, A., O'Connell, D. J., Armstrong, S. A. & Bracken, A. P., 01 Nov 2015, In : Genes and Development. 29, 21, p. 2231-43 13 p.

HPV16 Down-Regulates the Insulin-Like Growth Factor Binding Protein 2 to Promote Epithelial Invasion in Organotypic Cultures

Pickard, A., McDade, S. S., McFarland, M., McCluggage, W. G., Wheeler, C. M. & McCance, D. J., Jun 2015, In : PLoS Pathogens. 11, 6, 23 p., 1004988.

2014

Genome-wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress

McDade, S. S., Patel, D., Moran, M., Campbell, J., Fenwick, K., Kozarewa, I., Orr, N. J., Lord, C. J., Ashworth, A. A. & McCance, D. J., 02 Jun 2014, In : Nucleic Acids Research. 42, 10, p. 6270-6285 16 p.

Functional and genetic analysis of the colon cancer network

Emmert-Streib, F., de Matos Simoes, R., Glazko, G., McDade, S., Haibe-Kains, B., Holzinger, A., Dehmer, M. & Campbell, F. C., 16 May 2014, In : BMC Bioinformatics. 15 , Suppl 6, 15 p.

BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability

Savage, K. I., Matchett, K. B., Barros, E. M., Cooper, K. M., Irwin, G. W., Gorski, J. J., Orr, K. S., Vohhodina, J., Kavanagh, J. N., Madden, A. F., Powell, A., Manti, L., McDade, S. S., Park, B. H., Prise, K. M., McIntosh, S. A., Salto-Tellez, M., Richard, D. J., Elliott, C. T., Harkin, D. P. & McDade, S., 15 May 2014, In : Cancer Research. 74, 10, p. 2773-2784 12 p.

Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

Savage, K. I., Gorski, J. J., Barros, E. M., Irwin, G. W., Manti, L., Powell, A. J., Pellagatti, A., Lukashchuk, N., McCance, D. J., McCluggage, W. G., Schettino, G., Salto-Tellez, M., Boultwood, J., Richard, D. J., McDade, S. S. & Harkin, D. P., 08 May 2014, In : Molecular Cell. 54, 3, p. 445-459 15 p.

2013

AKT in Stromal Fibroblasts Controls Invasion of Epithelial Cells

Cichon, A-C., Pickard, A., McDade, S. S., Sharpe, D. J., Moran, M., James, J. A. & McCance, D. J., 14 Jul 2013, In : Oncotarget. 4, 7, p. 1103-1116 14 p.

Androgens and estrogens stimulate ribosome biogenesis in prostate and breast cancer cells in receptor dependent manner

Ray, S., Johnston, R., Campbell, D. C., Nugent, S., McDade, S. S., Waugh, D. & Panov, K. I., 19 Apr 2013, In : Gene. 526, 1, p. 46-53 8 p.

2012

Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk

Orr, N., Lemnrau, A., Cooke, R., Fletcher, O., Tomczyk, K., Jones, M., Johnson, N., Lord, C. J., Mitsopoulos, C., Zvelebil, M., McDade, S. S., Buck, G., Blancher, C., Trainer, A. H., James, P. A., Bojesen, S. E., Bokmand, S., Nevanlinna, H., Mattson, J., Friedman, E., Laitman, Y., Palli, D., Masala, G., Zanna, I., Ottini, L., Giannini, G., Hollestelle, A., Ouweland, A. M. W. V. D., Novaković, S., Krajc, M., Gago-Dominguez, M., Castelao, J. E., Olsson, H., Hedenfalk, I., Easton, D. F., Pharoah, P. D. P., Dunning, A. M., Bishop, D. T., Neuhausen, S. L., Steele, L., Houlston, R. S., Garcia-Closas, M., Ashworth, A., Swerdlow, A. J. & KConFab Consortium, 23 Sep 2012, In : Nature Genetics. 44, 11, p. 1182-4 3 p.

A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers

Natrajan, R., Mackay, A., Lambros, M. B., Weigelt, B., Wilkerson, P. M., Manie, E., Grigoriadis, A., A'hern, R., van der Groep, P., Kozarewa, I., Popova, T., Mariani, O., Turajlic, S., Furney, S. J., Marais, R., Rodruigues, D-N., Flora, A. C., Wai, P., Pawar, V., McDade, S., Carroll, J., Stoppa-Lyonnet, D., Green, A. R., Ellis, I. O., Swanton, C., van Diest, P., Delattre, O., Lord, C. J., Foulkes, W. D., Vincent-Salomon, A., Ashworth, A., Henri Stern, M. & Reis-Filho, J. S., May 2012, In : Journal of Pathology. 227, 1, p. 29-41 13 p.

Genome-wide analysis of p63 binding sites identifies AP-2 factors as co-regulators of epidermal differentiation

McDade, S., Henry, A., Pivato, G., Kozarewa, I., Mitspoulos, C., Fenwick, K., Assiotis, I., Hakas, J., Zvelebil, M., Orr, N., Lord, C., Patel, D., Ashworth, A. & McCance, D., May 2012, In : Nucleic Acids Research. 40, 15, p. 7190-7206 17 p.

Expression of the SEPT9_i4 isoform confers resistance to microtubule-interacting drugs

McDade, S. S., Chacko, A. D., Chanduloy, S., Church, S. W., Kennedy, R., Price, J., Hall, P. A. & Russell, S. E., 01 Apr 2012, In : Cellular Oncology. 35, 2, p. 85-93 9 p.

2011

Profiling of the BRCA1 transcriptome through microarray and ChIP-chip analysis

Gorski, J. J., Savage, K. I., Mulligan, J. M., McDade, S. S., Blayney, J. K., Ge, Z. & Harkin, P., 01 Dec 2011, In : Nucleic Acids Research. 39, 22, p. 9536-9548 13 p.

Evidence for Alteration of EZH2, BMI1, and KDM6A and Epigenetic Reprogramming in Human Papillomavirus Type 16 E6/E7-Expressing Keratinocytes

Hyland, P., McDade, S., McCloskey, R., Dickson, G., Authur, K., McCance, D. & Patel, D., Nov 2011, In : Journal of Virology. 85, 21, p. 10999-11006 8 p.

p63 maintains keratinocyte proliferative capacity through regulation of Skp2-p130 levels

McDade, S., Patel, D. & McCance, D., 01 May 2011, In : Journal of Cell Science. 124, 10, p. 1635-1643 9 p

The Delta Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer

Buckley, N., Conlon, S., Jirstrom, K., Kay, E. W., Crawford, N., O'Grady, A., Sheehan, K., McDade, S., Wang, C-W., McCance, D., Johnston, P., Kennedy, R., Harkin, P. & Mullan, P., 01 Mar 2011, In : Cancer Research. 71, 5, p. 1933-1944 12 p.

Role of Delta Np63 gamma in Epithelial to Mesenchymal Transition

Lindsay, J., McDade, S., Pickard, A., McCloskey, K. & McCance, D., 04 Feb 2011, In : Journal of Biological Chemistry. 286, 5, p. 3915-3924 10 p.

2010

MicroRNA 203 Expression in Keratinocytes Is Dependent on Regulation of p53 Levels by E6.

McKenna, D., McDade, S., Patel, D. & McCance, D., Oct 2010, In : Journal of Virology. 84, 20, p. 10644-10652 9 p.

The role of p63 in epidermal morphogenesis and neoplasia

McDade, S. S. & McCance, D. J., 2010, In : Biochemical society transactions. 38, Pt 1, p. 223-8 6 p.

2007

Translational control of SEPT9 isoforms is perturbed in disease

McDade, S. S., Hall, P. A. & Russell, H., 01 Apr 2007, In : Human Molecular Genetics. 16, 7, p. 742-752 11 p.

2005

The Septin-Binding Protein Anillin is Over-Expressed in Diverse Human Tumours

Hall, P. A., Todd, C. B., Hyland, P. L., McDade, S. S., Grabsch, H., Dattani, M., Hillan, K. J. & Russell, S. E. H., 01 Oct 2005, In : Clinical Cancer Research. 11, 19, p. 6780-6786 7 p.

SEPT9_v4 expression induces morphological change, increased motility and disturbed polarity

Chacko, A. D., Hyland, P. L., McDade, S. S., Hamilton, P. W., Russell, S. E. H. & Hall, P. A., Aug 2005, In : American Journal of Pathology. 206, 4, p. 458-465 8 p.