**7.2. Possible gene-therapies that improve the mitochondrial functions**

PGC-1α, which is encoded by the *PPARGC1A* gene, has been shown to be involved in the *de novo* synthesis of the NAD+ [172]. Recently, it was reported that lactamase β (LACTB) is a multifunctional protein, which suppresses tumors through its effects on the mitochondrial lipid metabolism [185]. LACTB is included in mitochondrial complex I and treatment of fibroblast cells with its siRNA reduces complex I activity [186]. It therefore works as an upregulator of NAD+ . As expected, multiple duplications of the GGAA-motif are present in the bidirectional promoter region between the *LACTB* (*MRPL56*) gene and the bidirectional partner *LOC107987798*. We confirmed that the duplicated GGAA-motif is present near the TSS of the human *PDSS2* gene, which encodes prenyl-diphosphatase synthase subunit 2, which is a modulator of the complex I–III and II–III [133]. The PDSS2 is required for the integrity of Coenzyme Q (CoQ) or ubiquinone, which can improve the mitochondrial functions [187]. Thus, PDSS2 would be one of the targets for novel anticancer agents [188, 189]. The introduction of the *LbNOX* gene, which encodes bacterial NADH oxidase, into HeLa cells via a lentiviral vector ameliorates the proliferative and metabolic defects caused by the impairment of the electron transport chain (ETC) [190].These lines of evidence suggest that NAD+ metabolism regulator encoding genes, including *PARP*, *PARG,* and *NAMPT*, as well as the *PPARGC1A*, *LACTB*, *PDSS2*, and *LbNOX* genes, could be applied or targeted in anti-cancer gene therapy.

Alternatively, TF-encoding genes can be applied to anti-cancer therapies that aid in the recovery of mitochondria. First, the transcription modulator CtBP might be artificially controlled to suppress oncogenesis or cancer progression [83, 84]. Second, because duplicated GGAAmotifs are present in the 5′-upstream regions of a number of DNA repair factor- and mitochondrial factor-encoding genes, GGAA-motif binding factors could upregulate the mitochondrial functions at the transcriptional level. Recently, it was reported that mouse Gabp, which is an ETS family protein, is required for mitochondrial biogenesis through the regulation of the *Tfb1m* gene [191], suggesting that a *GABP* expression vector might be designed and constructed for cancer treatment. The 5′-upstream regions of a number of human genes contain the GGAA-duplication, and it is a GC-box that is very frequently found near the GGAA-core motif [12]. Recently, it was reported that mutations on the ETS family protein-encoding *ERF* and *ERG* genes play roles in prostate oncogenesis [192], implying that imbalances in GGAAbinding TFs could lead to aberrant gene expression. In order to determine which TF-encoding genes should be chosen, the mechanisms through which each of these genes is differently regulated during tumorigenesis should be elucidated.
