Chapter 6 - MYC in Oncogenesis and as a Target for Cancer Therapies
Section snippets
C-MYC, MYCN, and MYCL: Three Versions of a Multifunctional Protein
The MYC gene was originally identified in avian retroviruses as the oncogene responsible for inducing myelocytomatosis in birds (Sheiness and Bishop, 1979). The cellular homologue, c-MYC, was found to be evolutionarily conserved (Vennström et al., 1982). Later, MYCN and MYCL were found amplified in neuroblastoma and in small cell lung cancer (SCLC), respectively (Henriksson and Luscher, 1996). These genes share the same general topography with the main open reading frame retained within the
Networking Is Key with Max Acting as the Spider in the Web
As previously mentioned, the MYC dimerization partner Max, identified in 1991, was found to be an essential heterodimerization partner for all known c-MYC functions (Blackwood & Eisenman, 1991, Shen-Li et al., 2000). It has an important role in embryonic development as mice lacking max die at day 5–6 of gestation (Gilladoga et al., 1992, Shen-Li et al., 2000). Max is highly conserved in vertebrate evolution and, with a half-life longer than 14 h, is constitutively expressed in a number of
MYC-Mediated Repression
Transcriptional repression by MYC is mainly mediated through protein–protein contacts, where MYC antagonizes the function of other transcriptional activators, without direct contact with the DNA (Kleine-Kohlbrecher et al., 2006). For instance, c-MYC-mediated inhibition of transcription can be conferred through interaction with TFII-I in the transcription machinery, binding at initiator elements (Roy et al., 1991). Together with observations that MYC-mediated repression by MYC-interacting
Induction of Apoptosis
As mentioned above, MYC is a multifunctional protein and one of its important functions is the potentiation of apoptosis in response to cellular stress (reviewed in Nilsson and Cleveland, 2003). Cyclin A and Odc are two potential mediators of MYC-induced apoptosis since Odc-blockage inhibits apoptosis in MYC-overexpressing cells and forced expression of Cyclin A is sufficient to induce apoptosis under low serum conditions (Hoang et al., 1994, Packham & Cleveland, 1994). Ectopic expression of
Regulation of Stemness
Analysis of transgenic mice with conditional expression of c-MYC or MYCN has shown that they are essential for normal developmental control of hematopoietic and neural stem cells, respectively (Knoepfler et al., 2002, Wilson et al., 2004). MYCN has been shown to be required for normal neural stem cell function whereas c-MYC deficiency results in accumulation of defective hematopoietic stem cells (HSCs) due to niche-dependent differentiation defects (Baena et al., 2007, Wilson et al., 2004). It
Oncogenic Properties
A major fraction of all human cancers display deregulated MYC activity (Nilsson & Cleveland, 2003, Ponzielli et al., 2005). Alterations include chromosomal translocations exemplified by the c-MYC-Immunoglobulin (Ig) fusion gene in BL (Hecht and Aster, 2000) and increased c-MYC expression due to gene amplification (Hogarty, 2003) as well as protein stabilization (Sears et al., 2000). Other oncogenic features are induction of genomic destabilization (Felsher & Bishop, 1999b, Mai et al., 1999),
No Transformation Without MYC?
Even though the generally accepted view is that cooperation of two oncoproteins such as MYC and ras are sufficient for cellular transformation (Land et al., 1983), this only holds true for murine cells, whereas additional events are required in human cells (Boehm et al., 2005, Hahn et al., 1999). The initially identified four events were expanded to six when the viral element (SV40 large T oncoprotein) was substituted for c-MYC. It was found that inactivation of tumor suppressor genes (p53,
MYC-Associated Cancers and Their Treatment
The MYC family genes are deregulated by different mechanisms in several human neoplasias of different origin, including diffuse large B cell lymphoma, multiple myeloma, colon cancer, glioblastoma, melanoma, ovarian cancer, and prostate cancer (Nesbit et al., 1999, Vita & Henriksson, 2006). However, the extent of MYC involvement in these malignancies varies depending on the staging and the cancer form (Caccia et al., 1984, Nesbit et al., 1999, Pelengaris & Khan, 2003, Vita & Henriksson, 2006).
Novel Therapies
The most frequently used anticancer drugs, including chemotherapeutics targeting topoisomerases, DNA-damaging agents, mitotic inhibitors, antimetabolites, and nucleotide analogues, suffer the disadvantage of causing resistance development (Herr & Debatin, 2001, Luqmani, 2005). This is most likely due to a deficient apoptotic program in tumor cells together with increased efflux and decreased influx of the drug, and increased DNA repair. In addition, the adverse effects such as induction of
Targeted Therapy: What Is in the Future for MYC?
Targeting MYC or the MYC pathway has emerged as a very attractive approach to search for cancer intervention. This is because MYC is frequently deregulated in human tumors and is even believed to be aberrantly expressed in a major fraction of all cancers (Hermeking, 2003, Pelengaris & Khan, 2003, Prochownik, 2004). Several new strategies are being investigated, some of which are more promising than others (Dang et al., 2009, Hermeking, 2003, Johnsen et al., 2009, Lu et al., 2003, Pelengaris &
Concluding Remarks
We have highlighted some of the most important MYC functions and presented an overview of current and future therapies for a few cancers with MYC gene activation. The need for new, more specific cancer therapies is met by an intense research activity using different approaches and strategies. In addition, aspects such as timing, cellular location, and dosing also have to be taken into account when designing novel anticancer treatments targeting MYC or the MYC pathway. Most likely a combination
Acknowledgments
We are grateful to Dr. Lars-Gunnar Larsson for critical reading of the manuscript and to our many colleagues for sharing our fascination with MYC. We apologize to colleagues whose work we were unable to cite due to the scope and space restrictions. Research from the authors’ laboratories are supported by grants from the Swedish Cancer Society, the Swedish Research Council, the Swedish Childhood Cancer Society, King Gustaf V Jubilee Foundation, Karolinska Institutet, and KICancer. MAH is
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