Cancer/Testis Antigens (CTAs) represent a group of
proteins whose expression under physiological conditions is restricted to testis but activated in many human
cancers. Also, it was observed that co-expression of multiple CTAs worsens the patient prognosis. Five CTAs were reported acting in mitochondria and we recently reported 147 transcripts encoded by 67 CTAs encoding for
proteins potentially targeted to mitochondria. Among them, we identified the two
isoforms encoded by CT55 for whom the function is poorly understood. First, we found that patients with
tumors expressing wild-type CT55 are associated with poor survival. Moreover, CT55 silencing decreases dramatically cell proliferation. Second, to investigate the role of CT55 on mitochondria, we first show that CT55 is localized to both mitochondria and endoplasmic reticulum (ER) due to the presence of an ambiguous N-terminal targeting signal. Then, we show that CT55 silencing decreases
mtDNA copy number and delays
mtDNA recovery after an acute depletion. Moreover, demethylation of CT55 promotor increases its expression, which in turn increases
mtDNA copy number. Finally, we measured the
mtDNA copy number in NCI-60 cell lines and screened for genes whose expression is strongly correlated to
mtDNA amount. We identified CT55 as the second highest correlated hit. Also, we show that compared to
siRNA scrambled control (siCtrl) treatment, CT55 specific
siRNA (siCT55) treatment down-regulates aerobic respiration, indicating that CT55 sustains mitochondrial respiration. Altogether, these data show for first time that CT55 acts on
mtDNA copy number, modulates mitochondrial activity to sustain
cancer cell proliferation.