Dicer Cooperates with p53 to Suppress DNA Damage and Skin Carcinogenesis in Mice

Abstract

Dicer is required for the maturation of microRNA, and loss of Dicer and miRNA processing has been found to alter numerous biological events during embryogenesis, including the development of mammalian skin and hair. We have previously examined the role of miRNA biogenesis in mouse embryonic fibroblasts and found that deletion of Dicer induces cell senescence regulated, in part, by the p53 tumor suppressor. Although Dicer and miRNA molecules are thought to have either oncogenic or tumor suppressing roles in various types of cancer, a role for Dicer and miRNAs in skin carcinogenesis has not been established. Here we show that perinatal ablation of Dicer in the skin of mice leads to loss of fur in adult mice, increased epidermal cell proliferation and apoptosis, and the accumulation of widespread DNA damage in epidermal cells. Co-ablation of Dicer and p53 did not alter the timing or extent of fur loss, but greatly reduced survival of Dicer-skin ablated mice, as these mice developed multiple and highly aggressive skin carcinomas. Our results describe a new mouse model for spontaneous basal and squamous cell tumorigenesis. Furthermore, our findings reveal that loss of Dicer in the epidermis induces extensive DNA damage, activation of the DNA damage response and p53-dependent apoptosis, and that Dicer and p53 cooperate to suppress mammalian skin carcinogenesis.

Association between the DICER rs1057035 Polymorphism and Cancer Risk: Evidence from a Meta-analysis of 1,2675 Individuals

“…DICER is a member of RNase enzymes and an important nuclease responsible for the cleavage of miRNA precursors (Liu et al, 2008). DICER possesses a complex role in cancer through its ability to regulate the maturation of miRNA (Lyle et al, 2014). Growing research suggests that dysregulated expression of DICER might play a vital role in cancer risk and prognosis (Caffrey et al, 2013;Avery-Kiejda et al, 2014;He et al, 2014).…”

WP1130 increases doxorubicin sensitivity in hepatocellular carcinoma cells through usp9x-dependent p53 degradation

“…p53 regulates a variety of cellular functions, including DNA repair, cell cycle arrest, and apoptosis [7][8][9]. It is well accepted that ubiquitination by E3 ubiquitin ligases plays an important role in p53 regulation via proteasomal degradation [10].…”

Cell survival is dicey without Dicer

“…Dicer ablation in untransformed murine fibroblasts or epidermis led to p53 activation and premature senescence or apoptosis, respectively. 8, 9 We detected an elevated frequency of p53 inactivation in B-cell lymphomas upon Dicer deletion, indicating an increase in p53 activation during transformation. 7 Deleting p53 or Arf (tumor suppressor and regulator of p53) delayed the premature senescence in fibroblasts, 9 and loss of p53 inhibited the apoptosis in epidermal cells 8 (Fig.…”