Recently, tumor suppressors p53 and WWOX were shown to regulate the apoptosis of glioblastoma cells (Chiang et al., 2012). WW domain-containing oxidoreductase, known as WWOX, FOR, or WOX1, is encoded by human or mouse WWOX/Wwox gene. This gene is located in chromosome 16q23.3–24.1, an area known as the common fragile site FRA16D. The full-length WWOX protein is composed of two N-terminal WW domains, a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a proapoptotic C-terminal tail D3 (Chang et al., 2001, 2007, 2010; Aqeilan et al., 2004, 2007; Hong et al., 2007; Salah et al., 2012) (Figure 1). WWOX may act as an alternative receptor for sex steroid hormones, since its SDR domain possesses an NSYK motif capable of interacting with androgen and estrogen (Chang et al., 2005a; Su et al., 2012).