**1. Introduction**

We have already learned that "cancer is a genetic disease". Recent high-impact research has shown the genomic/genetic differences between cancer and normal cells using methods such as next-generation sequencing [1, 2]. The analysis of the whole genome sequencing data will even enable us to predict the incidence of cancer in healthy individuals [3]. More

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

importantly, recent metabolome analyses have led to the rediscovery that metabolites could be biomarkers for cancer and its development [4]. The "Warburg effect", which was shown by Dr Otto Warburg over 60 years ago, is the most essential discovery in the field of cancer science [5]. The "Warburg effect" refers to abnormal metabolism in cancer, which mainly utilizes glucose to produce ATP by glycolysis. In this regard, "cancer is a metabolic disease". This is not only important as an indicator of tumors, but also as one of the essential characteristics of cancer [6, 7]. A number of lines of evidence, including dysregulated TCA (Krebs/Citrate)-cycle progression and the insufficient oxidative phosphorylation in cancer cells, suggest that mitochondrial dysfunction might precede the metabolic change [8]. Thus, "cancer must be a mitochondrial disease". In this chapter, which focuses on the causative factors that lead to mitochondrial dysfunction, we discuss whether "cancer is a transcriptional disease". Most of the genes (99%) that encode mitochondria or their function-associated proteins are contained in nuclear genomes [9]. The mitochondrial functions might be recovered or improved at a transcriptional level. In this chapter, we propose the establishment of novel chemo-/gene-therapies with no side effects, to force cancerous cells to regenerate into their normal differentiated state.

*VEGFR1* promoter region, which contains overlapping GGAA-motifs, is also regulated by CREB and EGR-binding elements [24]. Furthermore, the mouse *Ppp2r1a* gene promoter, which carries duplicated TTCC motifs, is regulated by Creb, Ets1, Ap2 alpha, and Sp1proteins [25]. Thus, multiple elements adjacent to duplicated GGAA-motifs may recruit various TFs to form a pre-initiation complex on the transcription start site (TSS) of TATA-less promoters. The transcription initiation system might be advantageous for a rapid response to stresses in a TATA-independent manner.

A New Insight into the Development of Novel Anti-Cancer Drugs that Improve the Expression…

http://dx.doi.org/10.5772/intechopen.71095

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**2.2. The duplicated GGAA-motifs that are contained in the 5′-upstream regions of** 

Duplicated GGAA-motifs are found in the 5′-upstream of the ISGs [20, 26, 27]. The GGAAmotifs are also harbored in the IFN-stimulated response element (ISRE)-like sequences [28, 29]. Thus, the duplicated GGAA-motifs near TSSs may play roles in controlling the expression of ISGs. The ISG-encoded proteins include TFs, immune modulators, apoptosis mediators, and anti-viral factors [30]. Previously, the duplicated GGAA-motifs in the regulatory regions of ISGs have been analyzed [31]. We surveyed the 5′-upstream regions in a number of ISGs to find GGAA-motifs within 500-bp upstream from the TSSs [32], and reported that IFNβ-inducible human *OAS1* promoter activity is regulated by binding of ELF-1 (which belongs to the ETS family proteins) to a duplicated GGAA-motif, and by its interaction with Sp1 and Rb proteins [33].

Collectively, the majority of the promoter regions from ISGs contain duplicated GGAA-motifs but rarely with TATA element. This suggests that the mechanism by which transcription is initiated differs from that of the house-keeping genes or genes that are essentially required, such as those that encode cell structure components. IFNs, the expression of which should be suppressed under normal conditions, only play important roles when it is necessary to fight against viral infection and oncogenesis. The duplicated GGAA-motifs might have contributed, through evolution, to the development of an immune response at the transcriptional level. In addition, GGAA-binding factors, which are associated with other TFs around TSSs, facilitate the expression of each ISG as appropriate, depending on the different signals that are induced by IFN.

**2.3. The duplicated GGAA-motifs in the 5′-upstream regions of the human DNA repair** 

The duplicated GGAA (TTCC) motif is present adjacent to the TSS of the human *TP53* gene [34], the expression of which is regulated by IFN-α and β [35]. IRF1 was reported to be a negative regulator of the human *TERT* promoter in response to IFN-γ [36]. In addition, IRF-5 has been shown to upregulate the expression of DNA repair/apoptosis-associated genes [37]. Moreover, DNA damage initiates an immune response that regulates DNA repair-associated genes [38]. These observations suggest that the immune responses and DNA damage responses might be co-dependent, and that the duplicated GGAA-motifs have important roles in controlling the expression of genes that encode DNA repair-associated factors in

It should be noted that the duplicated GGAA-motif is present in the promoter regions of the human *Poly(ADP-ribose) polymerase 1*(*PARP1*) [39, 40] and *XRCC1* [41] genes. The duplicated GGAA-motifs are present near the TSS of the *ADPRHL2* (*ARH3*) and the *ZC3HAV1* genes,

**immune response factor-encoding human genes**

**factor-encoding genes**

response to IFN-induced signals.
