Significance of prohibitin domain family in tumorigenesis and its implication in cancer diagnosis and treatment

Jie Yang,Qing-Yu He,Bin Li

doi:10.1038/s41419-018-0661-3

Abstract

Prohibitin (PHB) was originally isolated and characterized as an anti-proliferative gene in rat liver. The evolutionarily conserved PHB gene encodes two human protein isoforms with molecular weights of ~33 kDa, PHB1 and PHB2. PHB1 and PHB2 belong to the prohibitin domain family, and both are widely distributed in different cellular compartments such as the mitochondria, nucleus, and cell membrane. Most studies have confirmed differential expression of PHB1 and PHB2 in cancers compared to corresponding normal tissues. Furthermore, studies verified that PHB1 and PHB2 are involved in the biological processes of tumorigenesis, including cancer cell proliferation, apoptosis, and metastasis. Two small molecule inhibitors, Rocaglamide (RocA) and fluorizoline, derived from medicinal plants, were demonstrated to interact directly with PHB1 and thus inhibit the interaction of PHB with Raf-1, impeding Raf-1/ERK signaling cascades and significantly suppressing cancer cell metastasis. In addition, a short peptide ERAP and a natural product xanthohumol were shown to target PHB2 directly and prohibit cancer progression in estrogen-dependent cancers. As more efficient biomarkers and targets are urgently needed for cancer diagnosis and treatment, here we summarize the functional role of prohibitin domain family proteins, focusing on PHB1 and PHB2 in tumorigenesis and cancer development, with the expectation that targeting the prohibitin domain family will offer more clues for cancer therapy.

Highlights

The prohibitin (PHB) gene was originally isolated and characterized as a candidate anti-proliferative gene in rat Official journal of the Cell Death Differentiation AssociationYang et al Cell Death and Disease (2018)9:580 liver cells[1], and the homologous human gene maps to chromosome 17q21-212–4, encoding two ~33 KD proteins, PHB1 and PHB25
PHB1 located on the platelet membrane was demonstrated to be involved in PAR1-mediated human platelet aggregation[60, 61], while PHB2 located in rhabdomyosarcoma (RMS) cell membrane was reported to act as a regulator in IGFBP-6-induced RMS cell migration through its interaction with insulin-like growth factor (IGF)-binding protein (IGFBP)-610
As PHB2 is involved in estrogen-dependent cancers such as breast cancer, and BIG3 promotes cancer cell proliferation by inhibiting PHB2 nuclear translocation and promoting the activity of estrogen receptor α (ERα), the BIG3/PHB2 interaction is necessary for tumorigenesis[73, 74]

Summary

Introduction

The prohibitin (PHB) gene was originally isolated and characterized as a candidate anti-proliferative gene in rat Official journal of the Cell Death Differentiation AssociationYang et al Cell Death and Disease (2018)9:580 liver cells[1], and the homologous human gene maps to chromosome 17q21-212–4, encoding two ~33 KD proteins, PHB1 and PHB25. PHB1 located on the platelet membrane was demonstrated to be involved in PAR1-mediated human platelet aggregation[60, 61], while PHB2 located in rhabdomyosarcoma (RMS) cell membrane was reported to act as a regulator in IGFBP-6-induced RMS cell migration through its interaction with insulin-like growth factor (IGF)-binding protein (IGFBP)-610. Overexpression of PHB1 was verified in gallbladder cancer tissues, and further studies identified that PHB1 promotes cancer cell proliferation by activating ERK and downstream signaling pathways[68].

Results

Conclusion