NEW LINKS BETWEEN S-ACYLATION AND CANCER Jennifer Greaves and Luke H. Chamberlain Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom. Email: [email protected] or [email protected]
Conflict of interest statement: We declare that there are no conflicts of interest associated with this manuscript. Abstract S-acylation (also known as palmitoylation) is a major post-translational protein modification in all eukaryotic cells, involving the attachment of fatty acids onto cysteine residues. A variety of structural and signalling proteins are modified in this way, affecting their stability, membrane association and intracellular targeting. The enzymes that mediate S-acylation are encoded by genes belonging to the large (>20 genes) ZDHHC family. The importance of these enzymes for normal physiological function is highlighted by their links to a diverse range of disease states, including neurological disorders such as Huntington’s disease, schizophrenia and intellectual disability; diabetes and cancer. The recent study by YesteVelasco et al published in The Journal of Pathology highlights a novel tumour suppressor function for the zDHHC family: expression of zDHHC14 is decreased in testicular germ cell tumours, prostate cancer and a variety of other cancer types. This important finding further emphasises the emerging clinical significance of the zDHHC family of S-acylation enzymes.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/path.4339
This article is protected by copyright. All rights reserved
Keywords zDHHC, DHHC, S-acylation, palmitoylation, cancer Cellular proteins undergo a vast array of different chemical modifications to their amino acid backbone. S-acylation (also known as palmitoylation) is a post-translational modification (PTM) whereby fatty acids are attached to cysteine residues [1]. The effects of this modification on proteins include changes in their membrane partitioning, stability, interactions with other proteins, or localisation in the cell [2-5]. Furthermore, the dynamic nature of S-acylation allows for temporal control of these regulatory effects [3].
The zDHHC family of S-acyltransferases S-acylation was first identified as an important physiological PTM several decades ago [6], and many essential cellular proteins are modified in this way, such as G protein-coupled receptors, ion channels, Ras proteins and Gα subunits [3]. Identifying the enzymes that mediate S-acylation was a protracted process; however, the breakthrough came in 2004 with the discovery of the zDHHC family of mammalian S-acyltransferases [7, 8]. Twenty-four ZDHHC genes are present in the human genome, encoding proteins that are defined by the presence of a DHHC (apartate-histidine-histidine-cysteine) tetrapeptide within a 51 amino acid cysteine-rich (CR) domain [8]. The cysteine residue present in the DHHC motif is critical for enzyme function; indeed, it is proposed that the acyl chain is transferred from this cysteine on to the target cysteine of the substrate protein by a “ping pong” mechanism [9]. Although individual zDHHC enzymes display substrate specificity, substrates can generally be modified by more than one enzyme [8]. zDHHC enzymes locate principally to the outer surface of the endoplasmic reticulum and Golgi apparatus; however, a small number of isoforms are localised on distinct intracellular compartments, including endosomes and the plasma membrane [8].
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Links between zDHHC enzymes and disease There are several emerging links between dysregulation or dysfunction of zDHHC enzymes and disease states, including: Huntington’s disease (zDHHC17 and zDHHC13); schizophrenia (zDHHC8); intellectual disability (zDHHC9 and zDHHC15); and type 1 diabetes (zDHHC17) [8, 10]. Furthermore, connections between zDHHC enzymes and cancer have also been proposed: there is an increased copy number of a region of chromosome 5 that includes the ZDHHC11 gene in bladder [11] and lung cancers [12]; a reduced expression of zDHHC2 has been noted in gastric adenocarcinoma [13] and colorectal cancers [14]; and upregulation of zDHHC9 has also been noted in colorectal tumours [15]. Furthermore, the gene encoding zDHHC2 is located in a chromosomal region to which potential tumour suppressors map for many forms of cancer [15]. Although substrate targets of individual zDHHC enzymes have been identified, at present the disease mechanisms associated with zDHHC dysfunction are not known. In addition to these direct links between zDHHC expression levels and cancer, these enzymes are also central to tumourogenesis driven by oncogenic Hand N-Ras proteins. Plasma membrane delivery of these Ras isoforms requires tandem farnesylation and S-acylation, and the potential value of targeting these lipid modifications has been recognised for many years. Farnesyl transferase inhibitors have been assessed in clinical trials [16], and it is likely that zDHHC inhibitors will receive similar attention when they become available.
A tumour suppressor function for zDHHC14 The study by Yeste-Velasco et al [17] adds significant weight to the emerging links between zDHHC enzymes and cancer. Using SNP array analysis on a panel of samples that included 36 testicular germ cell tumours (TGCT) they revealed the loss of a small genomic region containing the ZDHHC14 gene in around 50% of TGCT cases; reduced expression of
This article is protected by copyright. All rights reserved
zDHHC14 in TGCT was confirmed at the mRNA and protein level. Furthermore, by analysing the “Oncomine” cancer microarray database, Yeste-Velasco et al noted that zDHHC14 expression was down-regulated in many cancers, and verified this experimentally in prostate cancer samples. Collectively, these findings highlighted a novel potential tumour suppressor function for zDHHC14, which were supported by cell-based and in vivo experiments. Yeste-Velasco et al showed that the over-expression of zDHHC14 induced apoptosis in HEK293 cells and a prostate cancer cell line, and suppressed xenograft tumour initiation. Similarly, using colony formation assays, they saw an increase in colony number and size in zDHHC14-depleted cells. These new findings provide an important and novel extension to existing knowledge surrounding zDHHC enzymes and cancer. We currently lack a clear understanding of the molecular mechanisms that link zDHHC expression levels to the initiation or progression of cancer. This idea is perhaps best exemplified by previous work that reported an up-regulation of zDHHC14 in certain other cancer types, as discussed by Yeste-Velasco et al [17]. A critical step in our understanding is to determine: what are the basic cellular functions of the individual zDHHC enzymes and what is their relevance to cancer? The sequence outside of the DHHC-CR domains of individual zDHHC enzymes are quite distinct, and “non-canonical” functions have been identified for some of these enzymes [8]. Yeste-Velasco et al found that a zDHHC14 mutant with a substitution of the catalytic cysteine in the DHHC motif induced less apoptosis than the wild-type protein, implying that S-acylation activity is important for the tumour suppressor activity of this enzyme. However, over-expression of this catalytically-dead mutant also increased apoptosis above control levels. While these findings might be due to the effects of protein overexpression, as suggested by Yeste-Velasco et al, it may also indicate that non-canonical activities contribute to the tumour suppressor function of zDHHC14.
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If the S-acylation activity of zDHHC14 is important for its tumour suppressor activity, it will be important to identify the downstream S-acylated substrates of this enzyme. Techniques have been established that mediate the purification of the S-acylated proteome from cells and tissues; thus, a clear strategy to identify the substrate targets of zDHHC14 would be to quantitatively compare the S-acylated proteome in control cells and cells depleted of zDHHC14. Once the zDHHC14 substrates are identified, it will be essential to determine whether any of them have tumour suppressor activity or link to tumour suppressor pathways; or whether the expression of mutant substrate proteins, engineered to be S-acylationindependent, rescue cellular changes caused by zDHHC14 down-regulation. Testing these ideas will help define the key enzyme-substrate relationships(s) underpinning the effects of modified zDHHC14 expression on cancer. Finally, it is important to consider if interplay between different zDHHC enzymes might be relevant to the initiation or progression of cancer. zDHHC enzymes exhibit a degree of substrate overlap, and so cellular S-acylation activities are the sum of the combined expression levels of multiple zDHHC enzymes. Therefore, the expression levels of zDHHC14 may be particularly important in some tissues (e.g. testicle and prostate), but not in others where different zDHHC expression profiles might better compensate for a loss of zDHHC14 expression. Indeed, the notion of interplay between different zDHHC enzymes might explain why up-regulation of zDHHC14 is oncogenic in certain tissues [17]. Similarly, there is potential for synergistic changes in the expression of multiple zDHHC enzymes to trigger oncogenecity. It is clear that fundamental advances in the zDHHC and S-acylation field are needed in order to understand disease processes. Critical advances will come from research that: (i) defines the substrate targets of all human zDHHC enzymes and highlights areas of potential redundancy or synergy; (ii) accurately maps the cell and tissue expression profiles of these
This article is protected by copyright. All rights reserved
zDHHC enzymes; and (iii) identifies novel, non-canonical activities of the zDHHC family. Addressing these questions will greatly enhance our knowledge of the mechanisms linking zDHHC enzyme dysregulation and dysfunction with disease, and will promote a clearer understanding of the novel tumour suppressor function of zDHHC14 proposed by YesteVelasco et al. [17].
Acknowledgements Work in the author’s laboratory is funded by the BBSRC (BB/J006432/1), MRC (G0601597/2), Wellcome Trust (WT094184MA), SULSA, and Diabetes UK (10/0004136).
Author Contribution statement Both authors contributed to conceiving and writing the manuscript.
References 1. Resh MD (2006) Trafficking and signaling by fatty‐acylated and prenylated proteins. Nature Chem Biol 2: 584‐590. 2. Greaves J & Chamberlain LH (2007) Palmitoylation‐dependent protein sorting. J Cell Biol 176: 249‐254. 3. Salaun C, Greaves J & Chamberlain LH (2010) The intracellular dynamic of protein palmitoylation. J Cell Biol 191: 1229‐1238, 4. Linder ME & Deschenes RJ (2007) Palmitoylation: policing protein stability and traffic. Nature Rev Mol Cell Biol 8: 74‐84. 5. Fukata Y & Fukata M (2010) Protein palmitoylation in neuronal development and synaptic plasticity. Nat Rev Neurosci 11: 161‐175. 6. Schlesinger MJ, Magee AI & Schmidt MF (1980) Fatty acid acylation of proteins in cultured cells. J Biol Chem 255: 10021‐10024. 7. Fukata M, Fukata Y, Adesnik H, Nicoll RA & Bredt DS (2004) Identification of PSD‐95 palmitoylating enzymes. Neuron 44: 987‐996. 8. Greaves J & Chamberlain LH (2011) DHHC palmitoyl transferases: substrate interactions and (patho)physiology. Trends Biochem Sci 36: 245‐253 9. Jennings BC & Linder ME (2012) DHHC Protein S‐Acyltransferases use a similar ping‐pong kinetic mechansim but display different acyl‐CoA specificities. J Biol Chem: 287: 7236‐7245. 10. Young FB, Butland SL, Sanders SS, Sutton LM & Hayden MR (2012) Putting proteins in their place: Palmitoylation in Huntington disease and other neuropsychiatric diseases. Prog Neurobiol 97: 220‐238.
This article is protected by copyright. All rights reserved
11. Yamamoto Y, Chochi Y, Matsuyama H, Eguchi S, Kawauchi S, Furuya T, Oga A, Kang JJ, Naito K & Sasaki K (2007) Gain of 5p15.33 Is Associated with Progression of Bladder Cancer. Oncology 72: 132‐138. 12. Kang JU, Koo SH, Kwon KC, Park JW & Kim JM (2008) Gain at chromosomal region 5p15.33, containing TERT, is the most frequent genetic event in early stages of non‐small cell lung cancer. Cancer Genet Cytogenet 182: 1‐11. 13. Yan S‐M, Tang J‐J, Huang C‐Y, Xi S‐Y, Huang M‐Y, Liang J‐Z, Jiang Y‐X, Li Y‐H, Zhou Z‐W, Ernberg I, et al. (2013) Reduced Expression of ZDHHC2 Is Associated with Lymph Node Metastasis and Poor Prognosis in Gastric Adenocarcinoma. PLOS One 8: e56366. 14. Oyama T, Miyoshi Y, Koyama K, Nakagawa H, Yamori T, Ito T, Matsuda H, Arakawa H & Nakamura Y (2000) Isolation of a novel gene on 8p21.3–22 whose expression is reduced significantly in human colorectal cancers with liver metastasis. Genes Chromosomes Cancer 29: 9‐15. 15. Birkenkamp‐Demtroder K, Christensen LL, Olesen SH, Frederiksen CM, Laiho P, Aaltonen LA, Laurberg S, Sørensen FB, Hagemann R & Ørntoft TF (2002) Gene expression in colorectal cancer. Cancer Res 62, 4352‐4363. 16. Basso AD, Kirschmeier P & Bishop WR (2006) Thematic review series: Lipid posttranslational modifications. Farnesyl transferase inhibitors. J Lipid Res 47, 15‐31. 17. YESTE‐VELASCO IRF et al., 2014 J Pathol, In Press
This article is protected by copyright. All rights reserved
Conflict of interest statement: We declare that there are no conflicts of interest associated with this manuscript. Abstract S-acylation (also known as palmitoylation) is a major post-translational protein modification in all eukaryotic cells, involving the attachment of fatty acids onto cysteine residues. A variety of structural and signalling proteins are modified in this way, affecting their stability, membrane association and intracellular targeting. The enzymes that mediate S-acylation are encoded by genes belonging to the large (>20 genes) ZDHHC family. The importance of these enzymes for normal physiological function is highlighted by their links to a diverse range of disease states, including neurological disorders such as Huntington’s disease, schizophrenia and intellectual disability; diabetes and cancer. The recent study by YesteVelasco et al published in The Journal of Pathology highlights a novel tumour suppressor function for the zDHHC family: expression of zDHHC14 is decreased in testicular germ cell tumours, prostate cancer and a variety of other cancer types. This important finding further emphasises the emerging clinical significance of the zDHHC family of S-acylation enzymes.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/path.4339
This article is protected by copyright. All rights reserved
Keywords zDHHC, DHHC, S-acylation, palmitoylation, cancer Cellular proteins undergo a vast array of different chemical modifications to their amino acid backbone. S-acylation (also known as palmitoylation) is a post-translational modification (PTM) whereby fatty acids are attached to cysteine residues [1]. The effects of this modification on proteins include changes in their membrane partitioning, stability, interactions with other proteins, or localisation in the cell [2-5]. Furthermore, the dynamic nature of S-acylation allows for temporal control of these regulatory effects [3].
The zDHHC family of S-acyltransferases S-acylation was first identified as an important physiological PTM several decades ago [6], and many essential cellular proteins are modified in this way, such as G protein-coupled receptors, ion channels, Ras proteins and Gα subunits [3]. Identifying the enzymes that mediate S-acylation was a protracted process; however, the breakthrough came in 2004 with the discovery of the zDHHC family of mammalian S-acyltransferases [7, 8]. Twenty-four ZDHHC genes are present in the human genome, encoding proteins that are defined by the presence of a DHHC (apartate-histidine-histidine-cysteine) tetrapeptide within a 51 amino acid cysteine-rich (CR) domain [8]. The cysteine residue present in the DHHC motif is critical for enzyme function; indeed, it is proposed that the acyl chain is transferred from this cysteine on to the target cysteine of the substrate protein by a “ping pong” mechanism [9]. Although individual zDHHC enzymes display substrate specificity, substrates can generally be modified by more than one enzyme [8]. zDHHC enzymes locate principally to the outer surface of the endoplasmic reticulum and Golgi apparatus; however, a small number of isoforms are localised on distinct intracellular compartments, including endosomes and the plasma membrane [8].
This article is protected by copyright. All rights reserved
Links between zDHHC enzymes and disease There are several emerging links between dysregulation or dysfunction of zDHHC enzymes and disease states, including: Huntington’s disease (zDHHC17 and zDHHC13); schizophrenia (zDHHC8); intellectual disability (zDHHC9 and zDHHC15); and type 1 diabetes (zDHHC17) [8, 10]. Furthermore, connections between zDHHC enzymes and cancer have also been proposed: there is an increased copy number of a region of chromosome 5 that includes the ZDHHC11 gene in bladder [11] and lung cancers [12]; a reduced expression of zDHHC2 has been noted in gastric adenocarcinoma [13] and colorectal cancers [14]; and upregulation of zDHHC9 has also been noted in colorectal tumours [15]. Furthermore, the gene encoding zDHHC2 is located in a chromosomal region to which potential tumour suppressors map for many forms of cancer [15]. Although substrate targets of individual zDHHC enzymes have been identified, at present the disease mechanisms associated with zDHHC dysfunction are not known. In addition to these direct links between zDHHC expression levels and cancer, these enzymes are also central to tumourogenesis driven by oncogenic Hand N-Ras proteins. Plasma membrane delivery of these Ras isoforms requires tandem farnesylation and S-acylation, and the potential value of targeting these lipid modifications has been recognised for many years. Farnesyl transferase inhibitors have been assessed in clinical trials [16], and it is likely that zDHHC inhibitors will receive similar attention when they become available.
A tumour suppressor function for zDHHC14 The study by Yeste-Velasco et al [17] adds significant weight to the emerging links between zDHHC enzymes and cancer. Using SNP array analysis on a panel of samples that included 36 testicular germ cell tumours (TGCT) they revealed the loss of a small genomic region containing the ZDHHC14 gene in around 50% of TGCT cases; reduced expression of
This article is protected by copyright. All rights reserved
zDHHC14 in TGCT was confirmed at the mRNA and protein level. Furthermore, by analysing the “Oncomine” cancer microarray database, Yeste-Velasco et al noted that zDHHC14 expression was down-regulated in many cancers, and verified this experimentally in prostate cancer samples. Collectively, these findings highlighted a novel potential tumour suppressor function for zDHHC14, which were supported by cell-based and in vivo experiments. Yeste-Velasco et al showed that the over-expression of zDHHC14 induced apoptosis in HEK293 cells and a prostate cancer cell line, and suppressed xenograft tumour initiation. Similarly, using colony formation assays, they saw an increase in colony number and size in zDHHC14-depleted cells. These new findings provide an important and novel extension to existing knowledge surrounding zDHHC enzymes and cancer. We currently lack a clear understanding of the molecular mechanisms that link zDHHC expression levels to the initiation or progression of cancer. This idea is perhaps best exemplified by previous work that reported an up-regulation of zDHHC14 in certain other cancer types, as discussed by Yeste-Velasco et al [17]. A critical step in our understanding is to determine: what are the basic cellular functions of the individual zDHHC enzymes and what is their relevance to cancer? The sequence outside of the DHHC-CR domains of individual zDHHC enzymes are quite distinct, and “non-canonical” functions have been identified for some of these enzymes [8]. Yeste-Velasco et al found that a zDHHC14 mutant with a substitution of the catalytic cysteine in the DHHC motif induced less apoptosis than the wild-type protein, implying that S-acylation activity is important for the tumour suppressor activity of this enzyme. However, over-expression of this catalytically-dead mutant also increased apoptosis above control levels. While these findings might be due to the effects of protein overexpression, as suggested by Yeste-Velasco et al, it may also indicate that non-canonical activities contribute to the tumour suppressor function of zDHHC14.
This article is protected by copyright. All rights reserved
If the S-acylation activity of zDHHC14 is important for its tumour suppressor activity, it will be important to identify the downstream S-acylated substrates of this enzyme. Techniques have been established that mediate the purification of the S-acylated proteome from cells and tissues; thus, a clear strategy to identify the substrate targets of zDHHC14 would be to quantitatively compare the S-acylated proteome in control cells and cells depleted of zDHHC14. Once the zDHHC14 substrates are identified, it will be essential to determine whether any of them have tumour suppressor activity or link to tumour suppressor pathways; or whether the expression of mutant substrate proteins, engineered to be S-acylationindependent, rescue cellular changes caused by zDHHC14 down-regulation. Testing these ideas will help define the key enzyme-substrate relationships(s) underpinning the effects of modified zDHHC14 expression on cancer. Finally, it is important to consider if interplay between different zDHHC enzymes might be relevant to the initiation or progression of cancer. zDHHC enzymes exhibit a degree of substrate overlap, and so cellular S-acylation activities are the sum of the combined expression levels of multiple zDHHC enzymes. Therefore, the expression levels of zDHHC14 may be particularly important in some tissues (e.g. testicle and prostate), but not in others where different zDHHC expression profiles might better compensate for a loss of zDHHC14 expression. Indeed, the notion of interplay between different zDHHC enzymes might explain why up-regulation of zDHHC14 is oncogenic in certain tissues [17]. Similarly, there is potential for synergistic changes in the expression of multiple zDHHC enzymes to trigger oncogenecity. It is clear that fundamental advances in the zDHHC and S-acylation field are needed in order to understand disease processes. Critical advances will come from research that: (i) defines the substrate targets of all human zDHHC enzymes and highlights areas of potential redundancy or synergy; (ii) accurately maps the cell and tissue expression profiles of these
This article is protected by copyright. All rights reserved
zDHHC enzymes; and (iii) identifies novel, non-canonical activities of the zDHHC family. Addressing these questions will greatly enhance our knowledge of the mechanisms linking zDHHC enzyme dysregulation and dysfunction with disease, and will promote a clearer understanding of the novel tumour suppressor function of zDHHC14 proposed by YesteVelasco et al. [17].
Acknowledgements Work in the author’s laboratory is funded by the BBSRC (BB/J006432/1), MRC (G0601597/2), Wellcome Trust (WT094184MA), SULSA, and Diabetes UK (10/0004136).
Author Contribution statement Both authors contributed to conceiving and writing the manuscript.
References 1. Resh MD (2006) Trafficking and signaling by fatty‐acylated and prenylated proteins. Nature Chem Biol 2: 584‐590. 2. Greaves J & Chamberlain LH (2007) Palmitoylation‐dependent protein sorting. J Cell Biol 176: 249‐254. 3. Salaun C, Greaves J & Chamberlain LH (2010) The intracellular dynamic of protein palmitoylation. J Cell Biol 191: 1229‐1238, 4. Linder ME & Deschenes RJ (2007) Palmitoylation: policing protein stability and traffic. Nature Rev Mol Cell Biol 8: 74‐84. 5. Fukata Y & Fukata M (2010) Protein palmitoylation in neuronal development and synaptic plasticity. Nat Rev Neurosci 11: 161‐175. 6. Schlesinger MJ, Magee AI & Schmidt MF (1980) Fatty acid acylation of proteins in cultured cells. J Biol Chem 255: 10021‐10024. 7. Fukata M, Fukata Y, Adesnik H, Nicoll RA & Bredt DS (2004) Identification of PSD‐95 palmitoylating enzymes. Neuron 44: 987‐996. 8. Greaves J & Chamberlain LH (2011) DHHC palmitoyl transferases: substrate interactions and (patho)physiology. Trends Biochem Sci 36: 245‐253 9. Jennings BC & Linder ME (2012) DHHC Protein S‐Acyltransferases use a similar ping‐pong kinetic mechansim but display different acyl‐CoA specificities. J Biol Chem: 287: 7236‐7245. 10. Young FB, Butland SL, Sanders SS, Sutton LM & Hayden MR (2012) Putting proteins in their place: Palmitoylation in Huntington disease and other neuropsychiatric diseases. Prog Neurobiol 97: 220‐238.
This article is protected by copyright. All rights reserved
11. Yamamoto Y, Chochi Y, Matsuyama H, Eguchi S, Kawauchi S, Furuya T, Oga A, Kang JJ, Naito K & Sasaki K (2007) Gain of 5p15.33 Is Associated with Progression of Bladder Cancer. Oncology 72: 132‐138. 12. Kang JU, Koo SH, Kwon KC, Park JW & Kim JM (2008) Gain at chromosomal region 5p15.33, containing TERT, is the most frequent genetic event in early stages of non‐small cell lung cancer. Cancer Genet Cytogenet 182: 1‐11. 13. Yan S‐M, Tang J‐J, Huang C‐Y, Xi S‐Y, Huang M‐Y, Liang J‐Z, Jiang Y‐X, Li Y‐H, Zhou Z‐W, Ernberg I, et al. (2013) Reduced Expression of ZDHHC2 Is Associated with Lymph Node Metastasis and Poor Prognosis in Gastric Adenocarcinoma. PLOS One 8: e56366. 14. Oyama T, Miyoshi Y, Koyama K, Nakagawa H, Yamori T, Ito T, Matsuda H, Arakawa H & Nakamura Y (2000) Isolation of a novel gene on 8p21.3–22 whose expression is reduced significantly in human colorectal cancers with liver metastasis. Genes Chromosomes Cancer 29: 9‐15. 15. Birkenkamp‐Demtroder K, Christensen LL, Olesen SH, Frederiksen CM, Laiho P, Aaltonen LA, Laurberg S, Sørensen FB, Hagemann R & Ørntoft TF (2002) Gene expression in colorectal cancer. Cancer Res 62, 4352‐4363. 16. Basso AD, Kirschmeier P & Bishop WR (2006) Thematic review series: Lipid posttranslational modifications. Farnesyl transferase inhibitors. J Lipid Res 47, 15‐31. 17. YESTE‐VELASCO IRF et al., 2014 J Pathol, In Press
This article is protected by copyright. All rights reserved
