Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathwayScience, May 17, 2019
Inhibition of oncogenic proteins represents a mainstay approach for cancer therapeutic development. By contrast, pharmacological modulation of tumor suppressor activity for the treatment of cancer has remained elusive. PTEN is a potent tumor suppressor gene, antagonizing the proto-oncogenic phosphoinositide 3-kinase (PI3K)–AKT signaling pathway and governing fundamental cellular processes. Cancer cells cannot afford to lose complete PTEN activity prematurely, because this would trigger cellular senescence, making PTEN an “obligate haploinsufficient” tumor suppressor gene. For this reason, PTEN is frequently dysregulated through monoallelic loss, aberrant subcellular localization, and/or posttranslational modification in human cancers as well as in cancer susceptibility syndromes such as PTEN hamartoma tumor syndrome (PHTS). Because PTEN overexpression in mice results in a tumor-suppressive metabolic state and life-span extension, the identification of molecular mechanisms to activate and reactivate PTEN function would offer important therapeutic opportunities for human health.
Although PTEN dimer formation and recruitment at the plasma membrane are indispensable for its function and activation, the mechanisms regulating these processes remain unknown. We thus sought to identify upstream regulators of PTEN dimerization and membrane localization, inhibition of which may restore PTEN activity and provide therapeutic opportunities against cancer.
Through immunoprecipitation followed by mass spectrometry analysis, we identified the HECT-type E3 ubiquitin ligase WWP1 as a physical PTEN interactor. We found that WWP1 specifically triggers nondegradative K27-linked polyubiquitination of PTEN to suppress its dimerization, membrane recruitment, and tumor-suppressive functions both in vitro and in vivo.
WWP1 is genetically amplified and frequently overexpressed in multiple cancers, including those of prostate, breast, and liver, which may lead to pleiotropic inactivation of PTEN. We found that WWP1 may be transcriptionally activated by the MYC proto-oncogene and that genetic depletion of Wwp1 in both Myc-driven mouse models of prostate cancer in vivo and cancer cells in vitro reactivates PTEN function, leading to inhibition of the PI3K-AKT pathway and MYC-driven tumorigenesis. Depletion of Wwp1 significantly reduced PI3K-AKT activity in mouse fibroblasts harboring monoallelic PTEN or PTEN mutations, as observed in PHTS patients. These findings demonstrate that WWP1 acts downstream of MYC and that perturbation of WWP1 is sufficient to restore PTEN tumor-suppressive activity.
We next identified indole-3-carbinol (I3C), a derivative of cruciferous vegetables, as a natural and potent WWP1 inhibitor through structure simulation and biochemical analyses. Pharmacological inactivation of WWP1 by I3C in either Myc-driven or Pten heterozygous mice reactivates PTEN, leading to potent suppression of tumorigenesis driven by the PI3K-AKT pathway. Therefore, genetic or pharmacological targeting of the WWP1-PTEN axis holds promise for patients affected by a number of cancers and other disorders associated with germline mutations of the PTENgene.
We have identified the MYC-WWP1 axis as a fundamental and evolutionary conserved regulatory pathway for PTEN and PI3K signaling. This pathway emerges not only as a rheostat for growth control in physiological conditions but also as a critical vulnerability hijacked for neoplastic transformation, which may be reversed by WWP1 pharmacological inactivation. These findings pave the way toward a long-sought tumor suppressor “reactivation” approach to cancer treatment. Because an increased expression level of MYC-WWP1 or PTEN impairment is widely pervasive in various human cancers, targeting this pathway toward PTEN reactivation may represent an “Achilles heel” of broad application.