PHLPP: a Janus-faced regulator in oncogenesis

PHLPP family is a type of serine/threonine phosphatase with tumor-suppressive functions. It is involved in a wide range of cellular processes, including the regulation of gene expression, cell cycle progression, cell migration, as well as cell survival and apoptosis. Recent studies have shown that PHLPP is dysregulated in various tumor tissues and plays a crucial role in oncogenesis. This review discusses the dual role of PHLPP in the regulation of signaling pathways, tumor microenvironments, and genomic stability, and examines the distribution, expression levels, and context-dependent tissue microenvironments of PHLPP in different cancer types. PHLPP often inhibits cancer progression by suppressing the PI3K/AKT/mTOR and RAF/MEK/ERK signaling pathways; however, recent identification efforts have yielded an unexpected finding. PHLPP promotes genomic instability through dephosphorylation of the oncoprotein MYC. Simultaneously, it worsens the immunosuppressive environment by suppressing the functions of neutrophils and effector T cells, while sustaining regulatory T cell function. It also inhibits the tumor suppressor p53, thereby facilitating oncogenic transformation. Furthermore, PHLPP regulates AKT and PKC isoforms, which exhibit context-dependent pro- or anti-tumorigenic roles. This "double-edged sword" functionality arises from the high dependency of PHLPP on tissue-specific contexts, such as inflammatory factors and oxidative stress, as well as substrate diversity and dynamic regulation within signaling networks. In this review, we summarize and discuss the complex mechanistic roles of PHLPP in cancer, which is crucial for understanding tumor progression and designing suitable PHLPP-targeted therapeutic strategies in the future.