Isoform-specific disruption of the TP73 gene reveals a critical role for TAp73γ in tumorigenesis via leptin
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eLife assessment
TP73 is a member of the p53 family of tumor suppressors. The authors provide compelling evidence that a TAp73-alpha to TAp73-gamma switch could be a frequent phenomenon in human cancers and provide novel evidence that TAp73-gamma has oncogenic functions via Leptin. The authors provide a substantial amount of high-quality data and convincingly demonstrate a novel function of this specific isoform of p73 in lipid metabolism and tumorigenesis.
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Abstract
TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α−η). ΔNp73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73α is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis. To test this, the TCGA SpliceSeq database was searched and showed that exon 11 (E11) exclusion occurs frequently in several human cancers. We also found that p73α to p73γ isoform switch resulting from E11 skipping occurs frequently in human prostate cancers and dog lymphomas. To determine whether p73α to p73γ isoform switch plays a role in tumorigenesis, CRISPR technology was used to generate multiple cancer cell lines and a mouse model in that Trp73 E11 is deleted. Surprisingly, we found that in E11-deificient cells, p73γ becomes the predominant isoform and exerts oncogenic activities by promoting cell proliferation and migration. In line with this, E11-deficient mice were more prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Additionally, we found that E11 - deficient mice phenocopies Trp73 -deficient mice with short lifespan, infertility, and chronic inflammation. Mechanistically, we showed that Leptin, a pleiotropic adipocytokine involved in energy metabolism and oncogenesis, was highly induced by p73γ,necessary for p73γ-mediated oncogenic activity, and associated with p73α to γ isoform switch in human prostate cancer and dog lymphoma. Finally, we showed that E11-knockout promoted, whereas knockdown of p73γ or Leptin suppressed, xenograft growth in mice. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism, which may be targeted for cancer management.
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eLife assessment
TP73 is a member of the p53 family of tumor suppressors. The authors provide compelling evidence that a TAp73-alpha to TAp73-gamma switch could be a frequent phenomenon in human cancers and provide novel evidence that TAp73-gamma has oncogenic functions via Leptin. The authors provide a substantial amount of high-quality data and convincingly demonstrate a novel function of this specific isoform of p73 in lipid metabolism and tumorigenesis.
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Reviewer #1 (Public Review):
TP73 is a member of the p53 family of tumor suppressors and is expressed as TAp73 and DNp73 and multiple C-terminal isoforms as a result of alternative splicing. In this study, the authors used isoform-specific disruption of the TP73 gene to investigate the physiological functions of p53 C-terminal isoforms, focussing on p73a and p73g. They identify an oncogenic role of TAp73-γ in tumorigenesis via regulating the expression of a novel target Leptin. Furthermore, they generated and characterized a mouse mode that expresses the TAp73 isoform γ but not α and shows how this splicing switch has oncogenic effects and causes metabolic defects. Overall, this is an important and well-done study uncovering a key role of TAp63-g in tumorigenesis via regulating Leptin expression.
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Reviewer #2 (Public Review):
The submitted manuscript deals with the intricate and complex network among different members of the p53 family with a specific focus on TAp73alpha and TAp73 gamma. The authors provide in vitro and in vivo evidence on the oncogenic role of TAp73 gamma which opposes the tumor suppressor activity of TAp73 alpha. Mice carrying exon 11 loss which is the molecular event leading to the switch to TAp73 gamma, are obese when compared to their counterparts. Interestingly, the authors propose that obesity in E11 mice relies on TAp73 gamma-induced aberrant expression of Leptin. The strength of the reported findings resides mainly in the combination of in vitro and in vivo approaches, while its weaknesses are related to the validation of reported findings in human tumoral contexts.
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Reviewer #3 (Public Review):
The authors employed a set of cell-based and animal studies with tumor model systems that harbor a genetically deleted specific isoform of p73 to identify a novel function of this isoform in the regulation of lipid metabolism and obese disorder, which are associated with tumorigenesis. Interestingly, this new function was found to be through the increase in leptin expression. This is probably the first study showing the connection of the p73 family members with leptin, a molecule that has been shown to play a critical role in obesity and metabolism. Overall, their findings are novel, interesting, and important.
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