Begell House Inc.
Onco Therapeutics
OT
2694-4642
1
1-2
2010
Genomic Imprinting and Transcription factor YY1
1-15
10.1615/ForumImmunDisTher.v1.i1-2.10
Joomyeong
Kim
Department of Biological Sciences, Louisiana State University, USA
genomic imprinting
YY1
DNA methylation
Peg3
Genomic imprinting is an unusual mechanism by which one allele is repressed on the basis of its parental origin. Imprinted genes are usually clustered in chromosomal regions, and a given domain is co-regulated through small genomic regions termed imprinting control regions (ICRs). ICRs obtain parental imprinting marks during gametogenesis in the form of DNA methylation and histone modifications. We previously discovered that unusual clusters of YY1 binding sites are localized within several ICRs, including Xist, Nespas, and Peg3, and also that these YY1-associated ICRs are all methylated during oogenesis. In the past few years, we have performed a series of in vivo YY1 knockdown experiments to investigate potential YY1 roles in DNA methylation of these ICRs. According to the latest results derived from conditional YY1 knockdown experiments, the reduced levels of YY1 during oogenesis resulted in a target-specific loss of DNA methylation on Peg3 and Xist. In contrast, the YY1 knockdown during spermatogenesis did not cause any major change in the DNA methylation levels of these ICRs. These studies suggest that YY1 likely plays a role in establishing DNA methylation of Peg3 and Xist during oogenesis, and further suggest that the clusters of YY1 binding sites of Peg3 and Xist might serve as a recruiting signal for de novo DNA methylation machineries.
Yin Yang 1 Is a Tumor Immune-Suppressor Gene Product
17-30
10.1615/ForumImmunDisTher.v1.i1-2.20
Stavroula
Baritaki
Center for Systems Biomedicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
TRAIL
Yin Yang 1
NF-kB
death receptors
apoptosis
drug resistance
Cancer patients initially respond to conventional therapies; however, a subset does not initially respond and others fail to respond to additional therapies. The mechanisms underlying resistance are not completely elucidated. We have identified Yin Yang 1 (YY1) as a pivotal regulator of tumor cell resistance to apoptosis by immunotherapeutics. YY1 has been shown to negatively regulate the transcription and expression of the TNF family receptors Fas and DR5, and maintains resistance to corresponding ligands, FasL and TRAIL, respectively. YY1 inhibition results in the upregulation of Fas and DR5 expression and sensitiza-tion to apoptosis. We have demonstrated the direct role of YY1 in the regulation of immune resistance, namely, reversal of resistance through inhibition of NF-κB activity, S-nitrosylation of YY1, and siRNA YY1. We have reported that treatment of immune-resistant tumor cells by various agents, such as chemotherapeutic drugs, proteasome inhibitors, the NF-κB inhibitor DHMEQ, and rituximab, all resulted in the inhibition of YY1 and sensitization to immunotherapy. Many tumors overexpress YY1, and YY1 levels correlate with tumor progression and are of bad prognostic significance. We introduce YY1 as a novel tumor immune-suppressor gene product and therefore inhibition of YY1 could be a novel approach to reverse tumor cell resistance to immunotherapy.
YY1 PcG function as a Potential cancer Therapeutic Target
31-50
10.1615/ForumImmunDisTher.v1.i1-2.30
Arindam
Basu
University of Pennsylvania, School of Veterinary Medicine, Department of Animal Biology, Philadelphia, Pennsylvania, USA
Suchita
Hodawadekar
University of Pennsylvania, School of Veterinary Medicine, Department of Animal Biology, Philadelphia, Pennsylvania, USA
Omozusi
Andrews
University of Pennsylvania, School of Veterinary Medicine, Department of Animal Biology, Philadelphia, Pennsylvania, USA
Antionette
Knox
University of Pennsylvania, School of Veterinary Medicine, Department of Animal Biology, Philadelphia, Pennsylvania, USA
Xuan
Pan
University of Pennsylvania, School of Veterinary Medicine, Department of Animal Biology, Philadelphia, Pennsylvania, USA
Frank
Wilkinson
Philadelphia University, School of Science and Health, Schoolhouse Lane and Henry Avenue, Philadelphia, Pennsylvania, USA
Michael L.
Atchison
University of Pennsylvania, School of Veterinary Medicine, Department of Animal Biology, USA
REPO domain
repression
cell death
apoptosis
Polycomb Group (PcG) proteins are overexpressed in a variety of cancers including hematopoietic malignancies, prostate cancer, and breast cancer, as well as others. PcG proteins are involved in stem cell self-renewal and can prevent stem cell exhaustion. Therapeutic targeting of PcG protein function, therefore, may have a positive impact on treatment of cancers caused by PcG dysfunction. For instance, the transcriptional silencing pathway used by PcG protein EZH2 is mechanistically linked with highly malignant behavior of prostate cancer, and reducing EZH2 levels through RNAi approaches reduces prostate cancer cell proliferation. In addition, pharmacologic disruption of PcG function can induce apoptosis of cancer cells. Targeting the mechanism of PcG recruitment to DNA would be an attractive avenue for therapy. We previously showed that transcription factor YY1 is a PcG protein that can recruit PcG proteins to DNA, leading to transcriptional repression. We identified the REPO domain, a small 25-amino-acid domain of YY1 that is necessary and sufficient for YY1 PcG function and for DNA recruitment of PcG proteins. Here we show that a synthetic peptide encoding the REPO domain can inhibit growth of both prostate cancer and Abelson-transformed pro-B cell lines. This inhibition is rapid and results in induction of cell death. Therefore, molecules that inhibit YY1 PcG function may be therapeutically useful.
YY1 as a Therapeutic Target in Cancer
51-64
10.1615/ForumImmunDisTher.v1.i1-2.40
Khimara
Naidoo
Academic Foundation Programme, St Thomas’ Hospital, Guys and St Thomas’ National Health Service Foundation Trust, London, United Kingdom
Richard J.
Byers
School of Cancer Imaging Sciences, Faculty of Medical and Human Sciences, The University of Manchester; and Department of Histopathology, Manchester Royal Infirmary, Manchester, United Kingdom
YY1
carcinogenesis
prognosis
diagnosis
cell cycle
apoptosis
TRAIL
NO
rituximab
targeted therapy
The transcription factor YY1 controls many divergent cellular processes, including cell proliferation and apoptosis. Because these processes are key to cancer development, the expression of YY1 is altered in many cancers, including lymphoma, prostatic cancer, osteosarcoma, ovarian cancer and leukemia. Its expression has been associated with development of the malignant phenotype, with tumor progression including metastasis, and with survival. Consequently, there has been recent interest in the possible role of YY1 as a therapeutic target. This article reviews the role of YY1 in the control of cell cycle and apoptosis, and provides a detailed discussion of its role in a range of human tumors. YY1 acts to inhibit Fas-mediated apoptosis, although this inhibition is reduced by treatment with rituximab. Similarly, YY1 acts to downregulate TRAIL-induced apoptosis, although this effect can be reversed by treatment with nitric oxide donors, suggesting a possible role for the use of nitric oxide and TRAIL agonists in chemoresistant tumors such as melanoma. Although research is in the early stages, the central position of YY1 in the control of key cellular processes and its association with several cancers renders particularly exciting therapeutic interventions.
Rationale for Targeting of YY1 in Drug-resistant Leukemias
65-79
10.1615/ForumImmunDisTher.v1.i1-2.50
James A.
McCubrey
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
Stephen L.
Abrams
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
William H.
Chappell
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
Linda S.
Steelman
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
Giovanni
Ligresti
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Nadia
Vella
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Andrea
Marconi
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences; and Section of Occupational Medicine, Department of Internal Medicine, University of Catania, Italy
Lidia
Proietti
Section of Occupational Medicine, Department of Internal Medicine, University of Catania, Italy
Ferdinando
Nicoletti
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Massimo
Libra
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania; Research Centre for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
Franca
Stivala
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
YY1
p53
ERK
drug resistance
chemotherapy
Cytokine-dependent, drug-sensitive, p53 wild-type (WT) FL5.12 cells and the doxorubicin-resistant derivative line (FL/Doxo) were used to determine the roles of the mechanisms by which p53 could alter Ying Yang 1 (YY1) transcription factor expression in early hematopoietic precursor cells. Drug resistance was associated with decreased p53 induction after doxorubicin treatment, which was caused by a higher level of proteosomal degradation of p53 and also resulted in a lower level of YY1 expression. Insertion of a dominant negative p53 gene further increased the resistance of the cells to chemotherapeutic drugs and also resulted in low levels of YY1 expression. Thus, in our system we could examine the effects of p53 and chemotherapeutic drugs on YY1 expression in a series of cells that were all derived from the common parental cell line. Doxorubicin increased the expression of the YY1 protein more in the parental cells, which have higher levels of WT p53, than in the doxorubicin-resistant cells. Thus, in our system of early hematopoietic cells YY1 expression was associated with functional p53 activity. In summary, our studies indicate that regulating YY1 activity may be a potential approach to regulate drug resistance.
Clinical Significance of the Inhibition of YY1 Activity and Expression by Therapeutic Anti-Cancer Antibodies
81-95
10.1615/ForumImmunDisTher.v1.i1-2.60
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Sara
Huerta-Yepez
Hospital Infantil de México Federico Gomez
Ali R.
Jazirehi
Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center; and Department of Surgery, University of California, Los Angeles, California, USA
Loredana
Militello
Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
Norio
Uematsu
BioMedics Japan Inc., Bunkyo, Tokyo, Japan
Demetrios A.
Spandidos
Department of Applied Biochemistry and Immunology, Institute of Molecular Biology and Biotechnology, Laboratory of Clinical Virology, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
Stavroula
Baritaki
Center for Systems Biomedicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Mario I.
Vega
Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center IMSS, Mexico City, Mexico; Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, David Geffen School of
Medicine, University of California, Los Angeles
anti-CD20 signaling
NF-kB inactivation
drug resistance
Bcl-2 family
transcription repressor
A large number of hematologic malignancies of B-cell origin express the CD20 receptor on the cell surface. CD20 is expressed in the B-cell lineage and is absent in plasma cells. Antibodies directed against CD20 result in the elimination of normal and malignant B cells and, hence, led to the development of a therapeutic antibody, rituximab, that has been approved by the U.S. Food and Drug Administration for the treatment of B-non-Hodgkin's lymphoma (NHL). Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), in part, cause depletion of B cells by rituximab in vivo. In addition, we have found that rituximab and several novel anti-CD20 monoclonal antibodies signal the cells and inhibit several intracellular pathways. For instance, we have demonstrated that treatment of B-NHL cell lines with anti-CD20 monoclonal antibody (mAb) resulted in the inhibition of constitutively activated transcription factors NF-κB and Yin Yang 1 (YY1). Inhibition of YY1 by anti-CD20 mAb was caused, in part, by the inhibition of NF-κB and induction of the Raf-1 kinase inhibitor protein (RKIP). Inhibition of YY1 with siRNA YY1 resulted in sensitization of B-NHL to apoptosis by drugs. These findings demonstrate that anti-CD20 mAb-induced cell sensitization is the result of inhibition of YY1 activity and expression. Similar findings were observed with the humanized anti-CD20 mAb, BM-ca, and anti-CD80 mAb, galiximab. Hence, YY1 is suggested to be a therapeutic target that can be used in conjunction with anti-CD20 antibodies and other therapeutic antibodies in the reversal of resistance in B-NHL and other malignancies.
Yin Yang 1 and raf-1 Kinase Inhibitory Protein Status in Hepatocellular carcinoma: Future Perspectives
97-114
10.1615/ForumImmunDisTher.v1.i1-2.70
Natale
D'Alessandro
Pharmacology Unit, University of Palermo Department of Health Sciences and Mother and Child Care "Giuseppe D'Alessandro" Palermo, Italy
Lydia
Giannitrapani
Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy; Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Italy
Manuela
Labbozzetta
Pharmacology Unit, Department of Health Sciences and Mother and Child Care "G. D'Alessandro", University of Palermo; Department of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, Palermo, Italy
Paola
Poma
Pharmacology Unit, Department of Health Sciences and Mother and Child Care "G. D'Alessandro", University of Palermo; Department of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, Palermo, Italy
Luigi
Inguglia
Department STEBICEF, University of Palermo, Palermo, Italy; Euro Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
Ada Maria
Florena
Dipartimento di Patologia Umana, Universitü degli Studi di Palermo, Palermo
Rossana
Porcasi
Dipartimento di Patologia Umana, Universitü degli Studi di Palermo, Palermo
Melchiorre
Cervello
Institute for Biomedical Research and Innovation, Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR) Palermo, Italy
Giuseppe
Montalto
Dipartimento di Medicina Clinica e delle Patologie Emergenti, Universitü degli Studi di Palermo, Palermo
Monica
Notarbartolo
Pharmacology Unit, Department of Health Sciences and Mother and Child Care "G. D'Alessandro", University of Palermo; Palermo, Italy
hepatocellular carcinoma
Yin Yang 1
Raf-1 kinase inhibitor protein
YY1-associated protein
nuclear factor-kappaB
sorafenib
We focus on to the role of the transcription factors NF-κB and Yin Yang 1 (YY1) and of Raf-1 kinase inhibitory protein (RKIP) in hepatocellular carcinoma (HCC). YY1, whose expression is enhanced by NF-κB, favors tumorigenesis. RKIP inhibits the oncogenic activities of MAPK and NF-κB pathways and promotes drug-induced apoptosis. Mutual influences between YY1 and RKIP may exist and there is separate evidence that relevant increases in YY1 and reductions in RKIP occur in HCC. In a recent study on clinical HCC, we found that, indeed, the ratio of YY1 to RKIP mRNA and protein expression is very frequently profoundly inverted in tumors compared with adjacent tissues. Hyperactivation of YY1 in tumors was corroborated by its nuclear localization and by concomitant increases in the coactivator YY1AP. Overall, the alteration in the YY1-RKIP balance might represent, beside a marker of malignant progression, a target of therapeutic interventions in HCC, which will include application of NF-κB inhibitors, also in conjunction with the active agent sorafenib.
Computational Evaluation of Yin Yang 1 Transcript Levels in the Spectrum of B-cell Neoplasia
115-125
10.1615/ForumImmunDisTher.v1.i1-2.80
Massimo
Libra
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania; Research Centre for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
Elena
Torrisi
Department of Biomedical Sciences, University of Catania, Catania
Giancarlo
Castellano
Department of Biomedical Sciences, University of Catania, Catania
Ferdinando
Nicoletti
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Grazia
Malaponte
Department of Biomedical Sciences, University of Catania, Catania
Maria C.
Mazzarino
Department of Biomedical Sciences, University of Catania, Catania
Andrea
Marconi
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences; and Section of Occupational Medicine, Department of Internal Medicine, University of Catania, Italy
Lidia
Proietti
Section of Occupational Medicine, Department of Internal Medicine, University of Catania, Italy
Loredana
Militello
Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Franca
Stivala
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Silvana
Canevari
Fondazione IRCCS Istituto Nazionale dei Tumori; Unit of Molecular Therapies, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
non-Hodgkin's Lymphoma
Yin Yang 1 (YY1)
apoptosis
Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lympho-proliferative malignancies with variable patterns of behavior and response to treatments. Although many patients respond to conventional therapies, many relapse and become refractory to further treatments. Studies using B-NHL cell lines have shown that the Yin Yang 1 (YY1) transcription factor is implicated in the regulation of resistance to both chemotherapeutic and immunotherapeutic drugs. This study examined the involvement of YY1 in the spectrum of B-cell neoplasia. The transcript levels of YY1 were evaluated using two different data sets of publicly available microarrays for lymphoma tumor biopsy specimens. The findings revealed that YY1 expression levels increased in association with B-cell transformation, suggesting that YY1 may be involved in B-cell transformation and may give rise to Burkitt's lymphoma and diffuse large B-cell lymphoma.
Clinical Significance of YY1 Overexpression in Human Hematopoietic Malignancies
127-139
10.1615/ForumImmunDisTher.v1.i1-2.90
Sara
Huerta-Yepez
Hospital Infantil de México Federico Gomez
Loredana
Militello
Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
Stavroula
Baritaki
Center for Systems Biomedicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Clara M. Rivera
Pazos
Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez. Mexico City
Ma del Lourdes
Cabrera-Munoz
Departamento de Patologia, Hospital Infantil de Mexico, Federico Gomez
Mario I.
Vega
Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center IMSS, Mexico City, Mexico; Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, David Geffen School of
Medicine, University of California, Los Angeles
Massimo
Libra
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania; Research Centre for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
Grazia
Malaponte
Department of Biomedical Sciences, University of Catania, Catania
Silvana
Canevari
Fondazione IRCCS Istituto Nazionale dei Tumori; Unit of Molecular Therapies, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Giancarlo
Castellano
Department of Biomedical Sciences, University of Catania, Catania
Haiming
Chen
Institute for Myeloma and Bone Cancer Research, West Hollywood, CA, USA
James R.
Berenson
Institute for Myeloma and Bone Cancer Research, West Hollywood, CA, USA
multiple myeloma
Ying Yang 1
chemoresistance
Patients with multiple myeloma (MM) develop resistance to conventional therapies. The underlying molecular mechanism responsible for resistance is not clear. We have reported in solid tumors that transcription factor Yin Yang 1 (YY1) is overexpressed and regulates tumor cell resistance to apoptotic stimuli induced by chemo- and immunotherapeutic drugs. Therefore, we hypothesized that MM may overexpress YY1 and that its overexpression may be a poor prognostic factor. This hypothesis was tested by using both MM cell lines and MM derived from patients' bone marrow samples. MM cell lines showed overexpression of YY1 by immunohistochemistry (IHC). Bone marrow samples from patients with MM showed overexpression of YY1 by IHC as compared with low levels of YY1 in normal bone marrow samples. The intensity and frequency of cells expressing YY1 in both the cytoplasm and nucleus was significantly higher among patients with progressive disease compared with patients with stable and responsive disease. These findings demonstrate that the expression of YY1 in MM may correlate with prognosis. Furthermore, the findings suggest YY1 as a therapeutic target for intervention in the reversal of resistance and prevention of disease progression in patients with MM.
COMMENTARY. Biochemistry and Gene regulation of YY1
141-143
10.1615/ForumImmunDisTher.v1.i1-2.100
Thomas
Efferth
Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany
Kam C.
Yeung
Department of Biochemistry & Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio
Kazuo
Umezawa
Department of Molecular Target Medicine Screening Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
M. Zouhair
Atassi
Baylor College of Medicine,
Houston, TX 77030, USA
The session on biochemistry and gene regulation of YY1 focused on specific aspects of YY1 from basic science. The three presentations of this session were given by M. Atchison (Philadelphia, Pennsylvania, USA), J. Kim (Baton Rouge, Louisiana, USA), and H.J. Garban (Los Angeles, California, USA).
COMMENTARY. Role of YY1 in Pathogenesis of Cancer
145-148
10.1615/ForumImmunDisTher.v1.i1-2.110
Silvana
Canevari
Fondazione IRCCS Istituto Nazionale dei Tumori; Unit of Molecular Therapies, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Ferdinando
Nicoletti
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Claudio
Napoli
Department of General Pathology, Division of Clinical Pathology, 1st School of Medicine, II University of Naples, Naples
Demetrios A.
Spandidos
Department of Applied Biochemistry and Immunology, Institute of Molecular Biology and Biotechnology, Laboratory of Clinical Virology, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
COMMENTARY. Regulation of Drug and Immune Resistance by YY1 in Cancer
149-151
10.1615/ForumImmunDisTher.v1.i1-2.120
Natale
D'Alessandro
Pharmacology Unit, University of Palermo Department of Health Sciences and Mother and Child Care "Giuseppe D'Alessandro" Palermo, Italy
Maria C.
Mazzarino
Department of Biomedical Sciences, University of Catania, Catania
James A.
McCubrey
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
Drug resistance, especially multidrug resistance (MDR), remains a major and difficult problem to resolve in the therapy of many cancer types. This process has previously been investigated mainly in a "pharmacologic" manner focused on the ability of tumor cells to extrude or inactivate the cytotoxic agents or to modify their targets of action. Much attention has focused on the overexpression of multidrug efflux transporters such as P-glycoprotein (MDR1, ABCB1) and many others. Nevertheless, evidence suggests that the sole reversion of the overexpression of such transporters has clinical success only in a few situations. On the other hand, today it is recognized that clinical MDR is often a multifactorial and heterogeneous process; many different molecular alterations, known to be involved in the malignant transformation and progression, may also be responsible for tumor drug resistance. Clearly, induction of tumor cell killing is fundamental for the efficacy of anticancer drugs. Mechanisms of cellular protection from their attacks include the loss of pro-apoptotic factors (e.g., functional p53 or Bax) or the overexpression of antiapoptotic factors (e.g., Bcl-2, Bcl-XL, or IAPs [inhibitor of apoptosis proteins]). Moreover, the many mechanisms of drug resistance may coincide with those responsible for resistance to immunotherapy, because the drugs and the immunologic effectors often use common pathways to evoke tumor cell damage.
COMMENTARY. Diagnostic and Prognostic roles of YY1
153-154
10.1615/ForumImmunDisTher.v1.i1-2.130
Franca
Stivala
Section of Clinical Pathology and Molecular Oncology, Department of Biomedical Sciences, University of Catania, Catania, Italy
Massimo
Libra
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania; Research Centre for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
Several investigators have observed YY1 deregulation in numerous tumor types. YY1 overexpression and its role in cancer were largely discussed during all of the workshop sessions. The results reported underlined the diagnostic and prognostic significance of YY1 in solid and hematologic malignancies. In particular, the reported inversion in the ratio between YY1 and Raf-1 kinase inhibitor protein (RKIP) expression in hepatocellular carcinoma, compared with the adjacent nontumoral tissues suggests a direct/indirect regulatory role of YY1 in hepatocyte transformation.1 RKIP was reported to antagonize the oncogenic activities of different kinases in the MAPK and NF-κB activation pathways. Furthermore, Seligson et al. reported that YY1 protein levels are higher in prostate metastatic tissues than primary tumors; intriguingly, low YY1 levels correlated with a poorer outcome, suggesting that decreased YY1 expression may enhance the survival of metastatic prostate cancer cells.2 Finally, Byers et al. showed that YY1, at mRNA levels, is overexpressed in follicular lymphomas and in diffuse large B-cell lymphoma.3 Moreover, the authors demonstrated that this overexpression is linked with a shorter survival. These data are in agreement with the findings reported, whereby the significance of YY1 deregulation in NHL was reported.4 In the reported in silico analysis, the YY1 association with prognosis was evaluated only in high-grade lymphomas and overexpression was statistically and significantly associated with poorer outcome. Confirmation data at the protein level are needed to better clarify the important findings mentioned above.