TAp63 regulates oncogenic miR-155 to mediate migration and tumour growth

Abstract

miR-155 is an oncogenic microRNA which is upregulated in many solid cancers. The targets of miR-155 are well established, with over 100 confirmed mRNA targets. However, the regulation of miR-155 and the basis of its upregulation in cancer is not well understood. We have previously shown that miR-155 is regulated by p63, and here we investigate the role of the major p63 isoforms TAp63 and ΔNp63 in this regulation. When the TAp63 isoform was knocked down, or exogenously overexpressed, miR-155 levels were elevated in response to TAp63 knockdown or reduced in response to TAp63 overexpression. The ΔNp63 isoform is shown to directly bind to the p63 response element on the miR-155 host gene, and this binding is enriched when TAp63 is knocked down. This could indicate that TAp63 prevents ΔNp63 from binding to the miR-155 host gene. The knockdown of TAp63, and the subsequent elevation of miR-155, enhances migration and tumour growth similar to that seen when directly overexpressing miR-155. The migratory phenotype is abrogated when miR-155 is inhibited, indicating that miR-155 is responsible for the phenotypic effect of TAp63 knockdown.

TAp63gamma is required for the late stages of myogenesis

“…37,41,42 p63 and p73 proteins share more than 60% of amino acids identity within the DNA-binding domain and possibly regulate overlapping set of target genes. 37,[43][44][45][46][47][48][49][50][51] In muscle differentiation, the functions of the individual members are distinct but complementary: while p53 transactivates RB gene, p63 and p73 induce the transcription of p57, which maintains Rb in an active, hypo-phosphorylated state, 18 also allowing execution of the later steps in skeletal myogenesis. 16 So far, the engagement of p53 family members in myogenesis has been demonstrated only in the early stage of in vitro muscle differentiation linked to permanent cell cycle exit.…”

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

“…3,6,14,38. We have previously investigated the molecular mechanism of Itch recognition for the p63 transcription factor 39 in particular, because this powerful transcription factor is crucial for the development of epithelia, 31,[40][41][42][43][44][45] it is involved in cancer, [46][47][48][49][50][51][52][53][54][55][56][57][58][59] and when it is mutated it causes severe genetic diseases.…”

Association of SIRT1 and tumor suppressor gene TAp63 expression in head and neck squamous cell carcinoma

“…TAp63 expression levels in HNSCC cell lines did not appear to be related to the differentiation status of the cells. Therefore, tumor suppression by TAp63 may involve mechanisms other than induction of differentiation, such as suppression of cell migration and metastasis [47,48]. It should be noted that TAp63 was previously shown to upregulate the expression of SIRT1 [50]; this might explain the positive correlation between SIRT1 and TAp63 expression observed in this study.…”

“…5). TAp63 has been implicated in tumor suppression, in addition to epithelial differentiation [46][47][48][49] (Ref 39, for a review). Therefore, upregulation of TAp63 by SIRT1 could account for the tumor-suppressive function of SIRT1 in HNSCC, at least in part.…”