Abstract Prohibitin 1 (PHB1) is a mitochondrial chaperone protein that is evolutionarily conserved and ubiquitously expressed, and functions in the regulation of cell proliferation, metabolism, and mitochondrial homoeostasis. Biological roles of PHB1 include involvement in multiple other pathways related to their subcellular localization, including mitochondria, plasma membrane, endoplasmic reticulum, and the nucleus. Alterations in PHB1 expression levels are associated with cancer, aging, neurodegeneration, and heart and kidney diseases. PHB1 has exhibited anti-proliferative activity in the liver and was considered a tumor suppressor in some cancers, including breast, gastric, and prostate cancer. However, PHB1 expression is often increased in many cancers and its role in oncogenesis is not clearly understood. Herein, we summarize the functional roles of PHB1 in cancer development and the therapeutic approaches for targeting PHB1.
Keywords Prohibitin1, subcellular localization, tumor suppressor, cancer, oncogenesis
Introduction
Prohibitins (PHBs) are evolutionarily conserved proteins that are localized in different cellular compartments and their functions include tissue-specific activities. Two PHB gene families, PHB1 and PHB2, form heterodimeric complexes in the mitochondria, where they play a pivotal role as scaffold proteins and function to stabilize newly synthesized mitochondrial proteins.1,2) The phb gene belongs to the band_7 domain protein family and is located on chromosome 17q21, encoding PHB1 and PHB2, each consisting of 272 amino acid residues with a molecular weight of ~33 kDa (Fig. 1).1)
Although the biological role of PHB is most defined in mitochondria, recent studies have reported that these proteins are also involved in various signal transduction pathways related to their subcellular localization. PHBs have been found in the plasma membrane, endoplasmic reticulum, nucleus, and macrophage phagosomes, where they regulate multiple other pathways regulating cell physiology.1,3) PHB1 has been found in the cell membrane, where it was shown to act as a receptor for viruses or bacteria, promoting their entry into the host cells.4,5) PHB1 that was localized to the plasma membrane was reported to function as a cell surface receptor in the gastrointestinal tract, protecting against
infection and inflammation.6,7) PHBs found in the plasma membrane of T lymphocytes interact with Vi capsular polysaccharide and are implicated in T cell activation.8) In addition, PHB1 also localizes to the nucleus of certain cell types and interacts with several transcription factors, including retinoblastoma (Rb), E2F, and p53, which regulate the transcriptional activities of E2F and p53.
Previous reports have shown that the accumulation of PHB1 in the nucleus is associated with the induction of cell cycle arrest and inhibition of cell proliferation.
PHB1 has multiple roles in cell signaling pathways because PHB1 itself is regulated by the phosphorylation of several tyrosine and serine residues, tyrosine nitrosylations, palmitoylations, and O-GlcNAc modifications (Fig. 1).9) Recent studies have shown that phosphorylation of PHB1 at Thr258 activates C-Raf (Raf-1), and the heterodimerization of phospho-PHB1 (Thr258) with C-Raf is necessary for the activation of C-Raf by Ras.10,11) Furthermore, Src homology region 2 domain-containing phosphatase-1/2, a phosphatase that facilitates protein kinase B (PKB, also known as AKT) signaling and enhances insulin signaling, interacts with PHB1. AKT also phosphorylates PHB1 at Thr258, which in turn inhibits the interaction of Shp1/2 with PHB1, and thus inhibiting AKT signaling (Fig. 1).1,12) However, Insulin-induced phosphorylation of PHB1 at Tyr114 promotes its interaction with Shp1 and inhibits AKT signal transduction (Fig. 1).
The drugs targeting PHB1 may be utilized to develop therapeutic agents for cancer. Some natural products, including flavaglines isolated from Aglaia species directly interact with PHB1, and suppress cancer cell proliferation and metastasis by
#Corresponding author
Jin Won Yang, College of Pharmacy, Woosuk University, Jeonbuk, Republic of Korea
Tel: +82-63-290-1812; Fax: +82-63-290-1812 E-mail: [email protected]
inhibiting Ras-Raf-MEK-ERK signaling.13,14)
Although cellular localization facilitates varied PHB1 functions in different biological processes that are associated with multiple diseases, including cancers, cardiac, inflammatory, neurological, and metabolic diseases; the functional role of PHB1 in cancer biology is not fully understood. Herein, we summarize current advances in the functional roles of PHB1 in cancer biology.
Role of Prohibitin1 in Liver Cancer
McClung et al. originally identified that PHB1 expression was downregulated in regenerating rat liver after 2/3rd partial hepatectomy.
Thus, PHB1 has been reported to have antiproliferative activity and is considered a potential tumor suppressor.15)
Since the deletion of PHB1 leads to embryonic lethality, hepatocyte specific deletion of PHB1 in mice was carried out, which resulted in spontaneous injury, inflammation, bile duct metaplasia, and hepatocellular carcinoma (HCC).16) PHB1 expression was shown to be downregulated during chronic cholestatic liver injury induced by bile duct ligation in humans with primary biliary cirrhosis, biliary atresia, and Alagille syndrome.17) Phb1 heterozygote is susceptible to cholestasis related cholangiocarcinoma (CCA).18) Recently, Wei et al. have shown that the downregulation of PHB1 has an inverse correlation with cell proliferation in HCC and CCA, repressing E-Box driven gene expression, including that of a well-known oncoprotein c- MYC.19)
Hepatocyte specific phb1-knock out (KO) mice showed elevated neddylation levels. Neddylation is a post-translational modification, which conjugates the ubiquitin-like molecule neural precursor cell- expressed developmentally downregulated-8 (NEDD8) with substrate proteins, including Cullin-RING ligases (CRLs).20) Neddylation plays an important role in regulating many important biological processes, including tumorigenesis; and shows a positive correlation
with poor prognosis in HCC patients. Administration of small molecule neddylation inhibitor, MLN4924, reduced liver fibrosis and tumor size in phb1-KO mice (Table 1).21)
The RNA-sequencing analysis showed that the loss of PHB1 could upregulate genes related to invasion and metastasis of cancer, such as interleukin-8 (IL-8), platelet derived growth factor subunit A, matrix metalloproteinase-2, and transforming growth factor beta (TGF-beta)-1 in PHB1-silenced HepG2 cells (Table 1).22) Among them, the expression levels of IL-8 were highly induced in multiple liver and non-liver cancer cell lines.
Furthermore, IL-8 mRNA levels were increased in patients with HCC, and PHB1 mRNA levels inversely correlated with IL-8 mRNA levels in HCCs that had reduced PHB1 expression.22) IL- 8 is known as a proinflammatory CXC chemokine that accelerates neutrophil chemotaxis and leukocyte infiltration; and its overexpression has been shown to promote tumor progression, angiogenesis, metastasis, and survival signaling for cancer stem cells, indicating that IL-8 may be a therapeutic target as a pharmacodynamic biomarker in cancer.23-25) Overexpression of PHB1 has shown to downregulate IL-8 expression and secretion in HCC cell lines.
However, silencing PHB1 accelerated the nuclear accumulation of c-JUN and p65 by increasing the expression of c-Jun N-terminal kinase (JNK) and the activity levels of nuclear factor kappa-light- chain-enhancer of activated B (NF-κB); thus, promoting IL-8 expression, which enhanced the migration and invasion properties of liver cancer cell lines (Table 1).22)
Insulin like growth factor 2 (Igf2) and H19 are well-known imprinted genes; allele-specific H19 and Igf2 expression in the imprinted control region (ICR) is regulated by the CCCTC- binding factor (CTCF) using the DNA methylation-dependent mechanism.26,27) Igf2 mitogenic peptide was upregulated in many cancers, resulting in resistance to chemotherapy, worse prognosis, and promotion of HCC growth.28,29) The long noncoding RNA imprinted with the parentally expressed non-translated transcript Fig. 1. Domain structures of mammalian PHB1 and location of phosphorylation sites
(H19) has been found to be highly expressed in embryonic and malignant tissues; and its overexpression leads to cell proliferation, invasion, metastasis, and chemotherapy resistance in HCC.30,31) Human HCC tissues overexpressing H19 and Igf2 have been reported to exhibit reduced expression of PHB1 and CTCF and reduced ICR binding activity.32) Liver specific phb1-KO mice was also shown to induce the expression of tumor growth related genes, including H19 and Igf2. PHB1 cooperates with CTCF in ICR to inhibit the H19-Igf2 axis in HCC cell lines (Table 1).32)
Wnt/beta-catenin signaling is a highly conserved and essential pathway for normal development and tissue regeneration of various organs, including liver.33,34) The 19 mammalian Wnt proteins are regulated at the transcriptional and post-transcriptional levels, and the secreted Wnt protein interacts with co-receptors Frizzled/
Low-density lipoprotein receptor-related protein (LRP)5/6. Wnt proteins phosphorylate glycogen synthase kinase 3 beta on Ser9 by kinases, such as AKT, which activate WNT target genes, including CTNNB1, FAB123B, and LRP5 through stabilization and increased nuclear translocation of beta-catenin.35) Aberrant regulation of the Wnt signaling pathway plays a crucial role in inducing malignant transformation and malignant progression of cancer cells.36,37) The overactive Wnt/beta-catenin signaling pathway plays an important role in the initiation and progression of human liver cancer, including HCC, CCA, and hepatoblastoma.38,39) PHB1 has been shown to negatively regulate the canonical WNT signaling pathway.40) Multiple WNT ligands, including Wnt7a, Wnt10a, and Wnt16 were highly overexpressed in phb1-KO
mouse liver as compared to WT mouse liver (Table 1).40) Although the distinction in the pattern of Wnt ligand induction between PHB1-silenced HCC cells and phb1-KO mouse livers has been observed, primary hepatocytes from phb1-KO mouse liver and PHB1-silenced liver cancer cells showed a significant increase in the number of expressed WNT ligands. Specifically, binding of the transcription factor E2F1 was increased at the Wnt10a promoter in phb1-KO mouse livers and at the Wnt9A promoter in HepG2 cells (Table 1).40) PHB1 negatively regulated the canonical WNT-beta-catenin signaling pathway through inhibition of AKT and glycogen synthase kinase 3 beta (GSK- 3beta) in hepatocytes and liver cancer cell lines.40)
Risk factors for developing HCC include obesity, insulin resistance and type 2 diabetes, non-alcoholic steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD).41,42) Many molecular mechanisms related to the development of HCC are associated with adipose tissue inflammation and hepatic lipotoxicity.43) Transgenic mice overexpressing PHB1 in adipocytes have been reported to cause obesity and obesity-related metabolic dysregulation, steatohepatitis, and HCC in males, suggesting that intrinsic factors modulate gender differences in HCC development.2,43) Luteolin has various biological activities, including apoptotic activity and anti-proliferative activities against various cancer cells. Luteolin treatment of human hepatocyte Huh-7 cells induced apoptosis through mitochondrial oxygen radical damage, which reduced PHB1 levels.44)
Breast cancer
SRC-3 Inhibition of SRC-3 by PHB1 47)
AR Upregulation of AR by PHB1 52)
Skp2B Degradation of PHB1 by Skp2B 53), 54)
DRP-1 Dissociation with PHB1 48)
Prostate cancer
miR27a Reduction of PHB1 mRNA levels by miR27a 57)
TGF-beta Increased phosphorylation of PHB1 in the TGF beta-induced Ras-Raf-MEK-ERK pathway Hypophosphorylation of PHB1 in TGF beta-induced Smad pathway 1) Lung
cancer
S100A16 Upregulation of PHB1 by S100A16 72)
Raf1, 14-3-3 Replacement of 14-3-3 from Raf-1 by direct PHB1 Interaction with Raf-1 78)
Role of Prohibitin1 in Breast Cancer
Breast cancer (BC) is the most common cancer in women and is a heterogeneous hormone-related cancer. PHB1 is overexpressed in invasive breast carcinoma, and high PHB1 expression levels are associated with poor outcomes in patients with invasive breast cancer.45) The activation of estrogen receptor α (ERα) by estrogen promotes the proliferation and metastasis of breast cancer cells. In the nucleus, PHB1 acts as a potent transcriptional corepressor for ERα to attenuate breast cancer survival. PHB1 also promotes the efficacy of tamoxifen in the treatment of ERα positive patients (Table 1).46) Additionally, PHB1 has been implicated in inhibiting steroid receptor coactivator-3 (SRC-3), a co-activator of ERα to repress breast cancer progression (Table 1).47) Overexpression of PHB1 significantly leads to apoptosis induction in ER-positive breast cancer cells.46) However, the role of PHB1 has been controversial as PHB1 is over-expressed in invasive breast carcinomas.45)
Glucose deprivation was shown to upregulate PHB1 expression
and induce an increase in mitochondrial ROS, thereby inhibiting the invasion and migration of triple negative breast cancer (TNBC) cell line MDA-MB-231.48) Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, plays important roles in the regulation of mitochondrial division and apoptosis.49) The upregulation of PHB1 under glucose deprivation resulted in its dissociation from DRP-1 and a decrease in mitochondrial membrane potential, leading to intrinsic apoptotic cell death (Table 1).48)
The localization of PHB1 is strongly implicated in tumorigenesis as PHB1 is found in the mitochondria in normal epithelial breast cells, but is localized in the nucleus in invasive and noninvasive breast cancer cells.50) Although the role of androgen receptor (AR), that belongs to the steroid receptor superfamily, in breast cancer is conflicting; however, AR is strongly associated with ERα positive breast cancer prognosis.51) Recent studies have demonstrated that PHB1 up-regulated AR expression and suppressed cell proliferation in ER positive breast cancer cells (Table 1).52)
F-box protein Skp2B is a subunit of specific ubiquitin ligase Fig. 2. Molecular mechanism and pathophysiological effects of PHB1 in various cancers. Abbrreviations: prohibitin1, PHB1; c-jun N- terminal kinase, JNK; interleukin-8, IL-8; dynamin-related protein 1, DRP1; estrogen receptor , ER; transforming growth factor beta, TGF-beta;
neural precursor cell-expressed developmentally downregulated-8, NEDD8; insulin like growth factor 2, Igf2; dynamin-related protein, DRP;
androgen receptor, AR.
target the UTR of PHB1 and are involved in tumorigenesis. In many breast cancer cell lines, 3'-UTR of PHB1 has been mutated and its mutation is associated with miRNA binding sites. C>T polymorphism in the 3'-UTR of PHB1 has been reported to act as a breast cancer modulator in the Polish cohort associated with breast cancer gene 1 (BRCA1) mutations.56,57) In silico analysis showed that 3'-UTR mutations of PHB1 have been identified and are reported to function as putative binding sites for several miRNAs in breast cancer cell lines.57,58)
Role of Prohibitin1 in Prostate Cancer
Prostate cancer (PCa) is a heterogeneous disease of aging men, primarily driven by AR.59) AR, a hormone belonging to nuclear receptor superfamily, is activated by androgens (such as testosterone and dihydrotestosterone (DHT)) and is a major transcription factor in the biology of PCa, and even in advanced castrate-resistant PCa (CRPC). Previous studies have shown that treatment with DHT downregulated PHB1 protein expression in LNCaP prostate cancer cells, and RNA interference to knockdown PHB1 has shown to increase cell cycle initiation in LNCaP cells.60) On the contrary, overexpression of PHB1 reduced androgen-dependent prostate-specific antigen (PSA) gene transcription and prostate cancer cell growth.61) Previous studies also demonstrated that PHB1 enhances the efficiency of androgen antagonists by inducing the recruitment of PHB and ATP dependent helicase BRG1 to androgen reactive elements, which inhibits the translocation of AR and induces antagonist-mediated growth inhibition of PCa cells.62)
In PCa, TGF-beta has a dual effect on apoptosis and cell invasion. TGF-beta functions as a tumor suppressor in the early stages of PCa while it induces metastasis and invasion of PCa during cancer progression. TGF-beta has also been shown to induce the Raf-MEK-ERK pathway, leading to the phosphorylation of PHB1, and thus promoting cell survival and invasion. However, TGF-induced Smad signal transduction upregulates 14-3-3 protein, resulting in hypophosphorylation of PHB1 that promotes apoptosis (Table 1).1)
and were used as biomarkers to monitor disease progression in PCa.59,63) Differential expression of miRNAs plays a crucial role in distinguishing benign from malignant disease. The AR signaling axis is implicated in the dysregulation of miRNA in both PCa and CRPC.63) miRNAs affect the AR signaling axis by direct targeting of 3-UTR of AR and/or indirect regulation of AR expression and activity.59) AR can directly modulate miRNA expression by binding to androgen response elements (AREs) within the cis regulatory regions that regulate miRNA gene expression.64) AR has been reported to induce transcription of miR-21 in androgen-responsive PCa resulting in direct regulation of PCa cell proliferation.65) Particularly, miR27a, which is encoded in an intergenic cluster with miR23a and miR-24-2, was upregulated by the androgens;
elevated miR27a reduced PHB1 mRNA and protein levels by targeting the 3'-UTR of PHB, resulting in increased PC cell growth (Table 1).57)
Role of Prohibitin1 in Lung Cancer
Lung cancer is the most commonly diagnosed cancer in the world, and it represents a main medical problem. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer (85% of lung cancers); 15% of lung cancers are classified as small cell lung cancers (SCLC), which include three histological subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.66,67) PHB1 levels are upregulated in NSCLC tissues as compared to the normal lung tissue and are closely associated with clinically aggressive phenotypes. In various NSCLC cell lines, total PHB1 protein expression levels are significantly upregulated, however, its subcellular localization is different, and the expression levels of membrane-associated PHB1 are reduced in all NSCLC cell lines as compared to BEAS-2B, human lung epithelial cells.68) Recent reports have shown that an increase in PHB1 expression levels is associated with poorer overall survival in patients with NSCLC. In addition, a unique nanoparticle platform composed of PHB1 siRNA inhibited lung tumor growth in xenograft models. In addition, the combination of PHB1 siRNA nanoparticles with cisplatin, a drug commonly used in the
treatment of NSCLC, significantly inhibited lung tumor growth.69) PHB1 has been reported to regulate survival in SCLC during metastasis of SCLC to the brain. S100A16, a member of the S100 family and a partner of the Annexin family of proteins, is upregulated in various tumors; elevated S100A16 in SCLC brain metastasis results in an increase in SCLC survival.70,71) S100A16 upregulates PHB1 expression to maintain mitochondrial membrane potential and promote SCLC cell survival. PHB1 silencing has been shown to reduce cell survival in S100A16 overexpressing SCLC cells (Table 1).72)
Post-translational modifications, such as phosphorylation, glycosylation, ubiquitylation, and small ubiquitin-related modifier (SUMO) play an important role in cell proliferation, differentiation, and cell death by regulating cellular signal transduction, stability, and trafficking of proteins.73-75) Post-translational modification of PHB1 is known to be regulated by phosphorylation, palmitoylation, O-GlcNAc modification, cysteine oxidation, and ubiquitination.
The human PHB1 protein undergoes two major forms of phosphorylation, such as serine/threonine phosphorylation and tyrosine phosphorylation; dysregulated phosphorylation of PHB1 is associated with various diseases, including diabetes, inflammation, and cancer. Particularly, phosphorylation or dephosphorylation of PHB1 at different amino acid residues leads to varied effects on cancer cell biology. Phosphorylation of PHB1 at Ser121, Tyr 259, Tyr114, and Thr258 is crucial for tumorigenesis.73,76,77) Direct PHB1 interaction with Raf-1 replaces 14-3-3 from Raf-1/14-3-3 complex by activated Ras to facilitate membrane localization; and consequently activates phosphorylation of Raf-1 at S338, resulting in epithelial cell adhesion and migration (Table 1).78) In addition, phosphorylation of PHB1 at Thr-258 in lipid rafts has been known to induce the activation of Raf-1 and Raf-1/ERK signaling pathway that promotes metastasis and invasion in lung cancer.10) Fluorizoline, a synthetic molecule that induces apoptosis by targeting PHB1, prevents Ras-Raf interaction and inhibits tumor growth and metastasis in KRAS-mediated lung cancers.79)
Conclusion
The potential of PHB1 to interact with various proteins makes it a unique protein that is implicated in various diseases, such as metabolic, inflammatory, and neurodegenerative diseases; thus, indicating that PHB1 may be utilized to develop promising targets for multiple disease states. Considering its various intracellular localizations and its translocation in response to diverse stimuli, the ability of PHB1 to function as an oncogene and tumor suppressor gene is complicated and different between normal and cancer cells. Depending on the type of cancer, multiple functions
of PHB1 can be defined; however, PHB1 is clinically relevant for the development of therapeutics. A better understanding of specific PHB1 functions within various cancer types may provide new avenues for the development of therapeutic options or molecular biomarkers for the diagnosis and prognosis of numerous cancer progressions.
Acknowledgment
This work was supported by Woosuk University and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2018R1C1B5085780).
Conflict of Interest
The authors who have taken part in this article declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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