The Role of Myc and the miR-17~92 Cluster in Histone Deacetylase Inhibitor Induced Apoptosis of Solid Tumors

Dominique R. Talbert, Robert L. Wappel, Diarmuid M. Moran, Scott A. Shell, Sarah S. Bacus

Quintiles Inc., Innovation, Translational R&D—Oncology, Westmont, USA.

DOI: 10.4236/jct.2013.44102                

Abstract

In recent years histone deacetylase inhibitors (HDACi’s) have emerged as promising therapeutics for cancer. While favorable responses to HDACi’s as single agents have been shown in several hematological malignancies, very little efficacy has been demonstrated in solid tumors. c-Myc (Myc), an oncoprotein commonly over-expressed in cancer, has been shown by several studies to play a critical role in HDACi-mediated cellular death. To expand upon these findings and determine the role that Myc plays in this process in solid tumors, we compared the effect of two HDAC inhibitors, SAHA and LAQ824, on the proliferation of solid tumor cell lines expressing high versus low levels of Myc. We found that cells expressing high levels of Myc were more sensitive to HDACi. In addition, there were significant differences in the type of response to HDACi treatment between the two cell types with prominent apoptosis in cells expressing higher levels of Myc while cell cycle arrest was more commonly observed in cells expressing lower levels of Myc. Interestingly, HDACi reduced the expression of Myc and one of its well-known oncogenic miRNA targets, miR-17~92 cluster, resulting in an increase in the expression of the master pro-apoptotic protein Bim. We propose that this novel mechanism may play a role in the potent anti-proliferative effects mediated by HDACi. Furthermore, these studies suggest that Myc expression could be used as a predictive biomarker to select patients with solid tumors who may be more responsive to HDACi treatment.

Keywords

Myc; miR-17~92; HDAC Inhibitors; Bim

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	S. B. Baylin and J. E. Ohm, “Epigenetic Gene Silencing in Cancer—A Mechanism for Early Oncogenic Pathway Addiction?” Nature Reviews Cancer, Vol. 6, No. 2, 2006, pp. 107-116. doi:10.1038/nrc1799
[2]	J. K. Choi and L. J. Howe, “Histone Acetylation: Truth of Consequences?” Biochemistry and Cell Biology, Vol. 87, No. 1, 2009, pp. 139-150. doi:10.1139/O08-112
[3]	J. E. Bolden, M. J. Peart and R. W. Johnstone, “Anticancer Activities of Histone Deacetylase Inhibitors,” Nature Reviews Drug Discovery, Vol. 5, No. 9, 2006, pp. 769-784. doi:10.1038/nrd2133
[4]	M. Duvic, R. Talpur, X. Ni, C. Zhang, P. Hazarika, C. Kelly, J. H. Chiao, J. F. Reilly, J. L. Ricker, V. M. Richon, et al., “Phase 2 Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) for Refractory Cutaneous TCell Lymphoma (CTCL),” Blood, Vol. 109, No. 1, 2007, pp. 31-39. doi:10.1182/blood-2006-06-025999
[5]	P. Atadja, M. Hsu, P. Kwon, N. Trogani, K. Bhalla and S. Remiszewski, “Molecular and Cellular Basis for the AntiProliferative Effects of the HDAC Inhibitor LAQ824,” Novartis Foundation Symposium, Vol. 259, 2004, pp. 249-266, discussion 266-268, 285-288. doi:10.1002/0470862637.ch19
[6]	P. A. Jones and S. B. Baylin, “The Epigenomics of Cancer,” Cell, Vol. 128, No. 4, 2007, pp. 683-692. doi:10.1016/j.cell.2007.01.029
[7]	W. Lutz, J. Leon and M. Eilers, “Contributions of Myc to Tumorigenesis,” Biochimica et Biophysica Acta, Vol. 1602, No. 1, 2002, pp. 61-71.
[8]	S. Pelengaris, M. Khan and G. Evan, “c-MYC: More than Just a Matter of Life and Death,” Nature Reviews Cancer, Vol. 2, No. 10, 2002, pp. 764-776. doi:10.1038/nrc904
[9]	H. A. Armelin, M. C. Armelin, K. Kelly, T. Stewart, P. Leder, B. H. Cochran and C. D. Stiles, “Functional Role for c-Myc in Mitogenic Response to Platelet-Derived Growth Factor,” Nature, Vol. 310, No. 5979, 1984, pp. 655-660. doi:10.1038/310655a0
[10]	S. O. Freytag, “Enforced Expression of the c-Myc Oncogene Inhibits Cell Differentiation by Precluding Entry into a Distinct Predifferentiation State in G0/G1,” Molecular and Cellular Biology, Vol. 8, No. 4, 1988, pp. 1614-1624.
[11]	G. I. Evan, A. H. Wyllie, C. S. Gilbert, T. D. Littlewood, H. Land, M. Brooks, C. M. Waters, L. Z. Penn and D. C. Hancock, “Induction of Apoptosis in Fibroblasts by cMyc Protein,” Cell, Vol. 69, No. 1, 1992, pp. 119-128. doi:10.1016/0092-8674(92)90123-T
[12]	M. H. Jamerson, M. D. Johnson and R. B. Dickson, “Of Mice and Myc: c-Myc and Mammary Tumorigenesis,” Journal of Mammary Gland Biology and Neoplasia, Vol. 9, No. 1, 2004, pp. 27-37. doi:10.1023/B:JOMG.0000023586.69263.0b
[13]	R. Visone and C. M. Croce, “MiRNAs and Cancer,” American Journal of Pathology, Vol. 174, No. 4, 2009, pp. 1131-1138. doi:10.2353/ajpath.2009.080794
[14]	W. C. Cho, “OncomiRs: The Discovery and Progress of microRNAs in Cancers,” Molecular Cancer, Vol. 6, 2007, 60. doi:10.1186/1476-4598-6-60
[15]	Y. Hayashita, H. Osada, Y. Tatematsu, H. Yamada, K. Yanagisawa, S. Tomida, Y. Yatabe, K. Kawahara, Y. Sekido and T. Takahashi, “A Polycistronic microRNA Cluster, miR-17-92, Is Overexpressed in Human Lung Cancers and Enhances Cell Proliferation,” Cancer Research, Vol. 65, No. 21, 2005, pp. 9628-9632. doi:10.1158/0008-5472.CAN-05-2352
[16]	L. He, J. M. Thomson, M. T. Hemann, E. HernandoMonge, D. Mu, S. Goodson, S. Powers, C. Cordon-Cardo, S. W. Lowe, G. J. Hannon, et al., “A Microrna Polycistron As a Potential Human Oncogene,” Nature, Vol. 435, No. 7043, 2005, pp. 828-833. doi:10.1038/nature03552
[17]	A. Ventura, A. G. Young, M. M. Winslow, L. Lintault, A. Meissner, S. J. Erkeland, J. Newman, R. T. Bronson, D. Crowley, J. R. Stone, et al., “Targeted Deletion Reveals Essential and Overlapping Functions of the miR-17 through 92 Family of miRNA Clusters,” Cell, Vol. 132, No. 5, 2008, pp. 875-886. doi:10.1016/j.cell.2008.02.019
[18]	V. Olive, I. Jiang and L. He, “mir-17-92, a Cluster of miRNAs in the Midst of the Cancer Network,” International Journal of Biochemistry & Cell Biology, Vol. 42, No. 8, 2009, pp. 1348-1354. doi:10.1016/j.biocel.2010.03.004
[19]	L. Hong, M. Lai, M. Chen, C. Xie, R. Liao, Y. J. Kang, C. Xiao, W. Y. Hu, J. Han and P. Sun, “The miR-17-92 Cluster of microRNAs Confers Tumorigenicity by Inhibiting Oncogene-Induced Senescence,” Cancer Research, Vol. 70, No. 21, pp. 8547-8557. doi:10.1158/0008-5472.CAN-10-1938
[20]	M. Dews, A. Homayouni, D. Yu, D. Murphy, C. Sevignani, E. Wentzel, E. E. Furth, W. M. Lee, G. H. Enders, J. T. Mendell, et al., “Augmentation of Tumor Angiogenesis by a Myc-Activated microRNA Cluster,” Nature Genetics, Vol. 38, No. 9, 2006, pp. 1060-1065. doi:10.1038/ng1855
[21]	A. Ota, H. Tagawa, S. Karnan, S. Tsuzuki, A. Karpas, S. Kira, Y. Yoshida and M. Seto, “Identification and Characterization of a Novel Gene, C13orf25, as a Target for 13q31-q32 Amplification in Malignant Lymphoma,” Cancer Research, Vol. 64, No. 9, 2004, pp. 3087-3095. doi:10.1158/0008-5472.CAN-03-3773
[22]	K. A. O’Donnell, E. A. Wentzel, K. I. Zeller, C. V. Dang and J. T. Mendell, “c-Myc-Regulated microRNAs Modulate E2F1 Expression,” Nature, Vol. 435, No. 7043, 2005, pp. 839-843. doi:10.1038/nature03677
[23]	Y. Sylvestre, V. De Guire, E. Querido, U. K. Mukhopadhyay, V. Bourdeau, F. Major, G. Ferbeyre and P. Chartrand, “An E2F/miR-20a Autoregulatory Feedback Loop,” Journal of Biological Chemistry, Vol. 282, No. 4, 2007, pp. 2135-2143. doi:10.1074/jbc.M608939200
[24]	P. Mu, Y. C. Han, D. Betel, E. Yao, M. Squatrito, P. Ogrodowski, E. de Stanchina, A. D’Andrea, C. Sander and A. Ventura, “Genetic Dissection of the miR-17~92 Cluster of microRNAs in Myc-Induced B-Cell Lymphomas,” Genes & Development, Vol. 23, No. 24, 2009, pp. 2806-2811. doi:10.1101/gad.1872909
[25]	L. Fontana, M. E. Fiori, S. Albini, L. Cifaldi, S. Giovinazzi, M. Forloni, R. Boldrini, A. Donfrancesco, V. Federici, P. Giacomini, et al., “Antagomir-17-5p Abolishes the Growth of Therapy-Resistant Neuroblastoma through p21 and BIM,” PLoS One, Vol. 3, No. 5, 2008, p. e2236. doi:10.1371/journal.pone.0002236
[26]	C. Xiao, L. Srinivasan, D. P. Calado, H. C. Patterson, B. Zhang, J. Wang, J. M. Henderson, J. L. Kutok and K. Rajewsky, “Lymphoproliferative Disease and Autoimmunity in Mice with Increased miR-17-92 Expression in Lymphocytes,” Nature Immunology, Vol. 9, No. 4, 2008, pp. 405-414. doi:10.1038/ni1575
[27]	S. Fotheringham, M. T. Epping, L. Stimson, O. Khan, V. Wood, F. Pezzella, R. Bernards and N. B. La Thangue, “Genome-Wide Loss-of-Function Screen Reveals an Important Role for the Proteasome in HDAC Inhibitor-Induced Apoptosis,” Cancer Cell, Vol. 15, No. 1, 2009, pp. 57-66. doi:10.1016/j.ccr.2008.12.001
[28]	S. K. Seo, H. O. Jin, S. H. Woo, Y. S. Kim, S. An, J. H. Lee, S. I. Hong, K. H. Lee, T. B. Choe and I. C. Park, “Histone Deacetylase Inhibitors Sensitize Human NonSmall Cell Lung Cancer Cells to Ionizing Radiation through Acetyl p53-Mediated c-myc Down-Regulation,” Journal of Thoracic Oncology, Vol. 6, No. 8, pp. 1313-1319. doi:10.1097/JTO.0b013e318220caff
[29]	X. Jiang, Y. H. Tsang and Q. Yu, “c-Myc Overexpression sensitizes Bim-Mediated Bax Activation for Apoptosis Induced by Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) through Regulating Bcl-2/ Bcl-xL Expression,” International Journal of Biochemistry & Cell Biology, Vol. 39, No. 5, 2007, pp. 1016-1025. doi:10.1016/j.biocel.2007.01.024
[30]	B. Brodska, P. Otevrelova and I. Kalousek, “Variations in c-Myc and p21WAF1 Expression Protect Normal Peripheral Blood Lymphocytes against BimEL-Mediated Cell Death,” Cell Biochemistry & Function, Vol. 27, No. 3, 2009, pp. 167-175. doi:10.1002/cbf.1552
[31]	S. K. Oster, D. Y. Mao, J. Kennedy and L. Z. Penn, “Functional Analysis of the N-Terminal Domain of the Myc Oncoprotein,” Oncogene, Vol. 22, No. 13, 2003, pp. 1998-2010. doi:10.1038/sj.onc.1206228
[32]	L. Kretzner, A. Scuto, P. M. Dino, C. M. Kowolik, J. Wu, P. Ventura, R. Jove, S. J. Forman, Y. Yen and M. H. Kirschbaum, “Combining Histone Deacetylase Inhibitor Vorinostat with Aurora Kinase Inhibitors Enhances Lymphoma Cell Killing with Repression of c-Myc, hTERT, and microRNA Levels,” Cancer Research, Vol. 71, No. 11, 2011, pp. 3912-3920. doi:10.1158/0008-5472.CAN-10-2259
[33]	K. J. Humphreys, L. Cobiac, R. K. Le Leu, M. B. Van der Hoek and M. Z. Michael, “Histone Deacetylase Inhibition in Colorectal Cancer Cells Reveals Competing Roles for Members of the Oncogenic miR-17-92 Cluster,” Molecular Carcinogenesis, Vol. 52, No. 6, 2013, pp. 459-474. doi:10.1002/mc.21879
[34]	W. S. el-Deiry, J. W. Harper, P. M. O’Connor, V. E. Velculescu, C. E. Canman, J. Jackman, J. A. Pietenpol, M. Burrell, D. E. Hill, Y. Wang, et al., “WAF1/CIP1 Is Induced in p53-mediated G1 Arrest and Apoptosis,” Cancer Research, Vol. 54, No. 5, 1994, pp. 1169-1174.
[35]	L. O’Connor, A. Strasser, L. A. O’Reilly, G. Hausmann, J. M. Adams, S. Cory and D. C. Huang, “Bim: A Novel Member of the Bcl-2 Family that Promotes Apoptosis,” EMBO Journal, Vol. 17, No. 2, 1998, pp. 384-395. doi:10.1093/emboj/17.2.384
[36]	F. Petrocca, A. Vecchione and C. M. Croce, “Emerging Role of miR-106b-25/miR-17-92 Clusters in the Control of Transforming Growth Factor Beta Signaling,” Cancer Research, Vol. 68, No. 20, 2008, pp. 8191-8194. doi:10.1158/0008-5472.CAN-08-1768
[37]	M. D. Erisman, P. G. Rothberg, R. E. Diehl, C. C. Morse, J. M. Spandorfer and S. M. Astrin, “Deregulation of c-Myc Gene Expression in Human Colon Carcinoma Is Not Accompanied by Amplification or Rearrangement of the Gene,” Molecular and Cellular Biology, Vol. 5, No. 8, 1985, pp. 1969-1976.
[38]	A. C. Faber, D. Li, Y. Song, M. C. Liang, B. Y. Yeap, R. T. Bronson, E. Lifshits, Z. Chen, S. M. Maira, C. Garcia-Echeverria, et al., “Differential Induction of Apoptosis in HER2 and EGFR Addicted Cancers Following PI3K Inhibition,” Proceedings of the National Academy of Sciences USA, Vol. 106, No. 46, 2009, pp. 19503-19508. doi:10.1073/pnas.0905056106
[39]	M. Gorospe, C. Cirielli, X. Wang, P. Seth, M. C. Capogrossi and N. J. Holbrook, “p21(Waf1/Cip1) Protects against p53-Mediated Apoptosis of Human Melanoma Cells,” Oncogene, Vol. 14, No. 8, 1997, pp. 929-935. doi:10.1038/sj.onc.1200897
[40]	F. Bunz, A. Dutriaux, C. Lengauer, T. Waldman, S. Zhou, J. P. Brown, J. M. Sedivy, K. W. Kinzler and B. Vogelstein, “Requirement for p53 and p21 to Sustain G2 Arrest after DNA Damage,” Science, Vol. 282, No. 5393, 1998, pp. 1497-1501. doi:10.1126/science.282.5393.1497
[41]	T. Waldman, C. Lengauer, K. W. Kinzler and B. Vogelstein, “Uncoupling of S Phase and Mitosis Induced by Anticancer Agents in Cells Lacking p21,” Nature, Vol. 381, No. 6584, 1996, pp. 713-716. doi:10.1038/381713a0
[42]	X. Ma, H. H. Ezzeldin and R. B. Diasio, “Histone Deacetylase Inhibitors: Current Status and Overview of Recent Clinical Trials,” Drugs, Vol. 69, No. 14, 2009, pp. 1911-1934. doi:10.2165/11315680-000000000-00000