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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 4
| Issue : 1 | Page : 35-40 |
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Prohibitin gene regulation in cancer and its possible therapeutic potential
Mohammad Zeeshan Najm1, Sadaf2, Naseem Akhtar3, Poonam Kashyap4, Vyas M Shingatgeri5, Komal Sharma5, Anjali Raghav5, Vishal Kumar Rout5, Farah Parveen2
1 Xcode Life Sciences, Chennai, Tamil Nadu, India
2 Department of Biosciences, Jamia Millia Islamia, New Delhi, India
3 Department of Laboratory Medicine, Albaha University, Al Bahah, Saudi Arabia
4 Department of Obstetrics and Gynaecology, MAMC, New Delhi, India
5 School of Biological Science, Apeejay Stya University, Gurugram, Haryana, India
| Date of Submission | 11-May-2021 |
| Date of Acceptance | 28-Jun-2021 |
| Date of Web Publication | 31-Jul-2021 |
Correspondence Address:
Farah Parveen
Department of Biosciences, Jamia Millia Islamia, New Delhi.
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jco.jco_10_21
Prohibitin (PHB), an evolutionary conserved gene, is mapped at the chromosomal location 17q21–q22 and is present with two isoforms, namely, PHB1 and PHB2. Both of these isoforms have their individual roles in tumor suppression and cell proliferation. The presence of these isoforms is not restricted to single cellular organelle but can be located in the nucleus, mitochondria, and cytosol. Importantly, loss of heterozygosity in the prohibitin gene has been noted in a significant number of different cancer types. Along with this, there are other mutations that contribute to tumorigenesis and cancer cell proliferation. Sporadic breast cancer, lung cancer, and prostate cancer are a few examples in which regulation of PHB plays a major role. PHB has shown to be both up-regulated and down-regulated depending on the type of cancer or disease. PHB acts as the biomarker for several types of cancers and is also seen as a potential therapeutic target. Along with cancer, PHB has also been seen to play an important role in other diseases such as neurological diseases, cardiac diseases, and renal diseases. The link between PHB and a plethora of diseases opens a new window in which PHB can be actually targeted in treatment as well as disease management. Here, we review the regulation of PHB in different types of cancers along with its significant interaction in other disorders. Keywords: Alzheimer’s disease (AD), androgen receptor (AR), cancer, prohibitin (PHB)
How to cite this article:
Najm MZ, Sadaf, Akhtar N, Kashyap P, Shingatgeri VM, Sharma K, Raghav A, Rout VK, Parveen F. Prohibitin gene regulation in cancer and its possible therapeutic potential. J Curr Oncol 2021;4:35-40 |
| Introduction | |  |
Prohibitin (PHB) gene has been known to play an important role in human cellular senescence and tumor suppression. It was originally found in liver cells of rat in which it expressed antiproliferative activity. In humans, this gene encodes for two isoforms of proteins in the form of PHB 1 and PHB 2 and it has a molecular weight of ~33 kDa[1],[2] that comes under stomatin/prohibitin/flotillin/Hflk/C (SPFH) family domain.[3] The N-terminal domain contains hydrophobic alpha helix that plays a role in lipid raft formation and helps in protein–protein interactions.[4] The localization of the prohibitin gene PHB1 is diverse in the cell organelle; when present in the inner membrane of mitochondria, it interacts with PHB2 and stabilizes the mitochondria which later is involved with apoptosis.[5],[6] PHB1 present in the plasma membrane interacts with viral and other microorganisms and acts as receptor for entry into host cell.[7] PHB1 located in lipid raft of the plasma membrane interacts with Raf-1 and activates it. Raf-1 being oncogene activates ERK and leads to cancer progression.[8] In contrast, PHB2 localized in the membrane has been found to have a role in cancer cell migration.[9] In the nucleus, PHB1 binds to various transcription factors, such as PHB1 located in p53, E2F, and pRb.[10] PHB2 in the nucleus is involved in the protection of centromeric cohesion and promotes cell growth. After several studies and researches, it has been identified that this gene has significance in tumorigenesis, cancer cell proliferation, metastasis, and apoptosis.[11],[12],[13],[14] The functional domains of prohibitin, namely, retinoblastoma (Rb) and E2F domains, have been found to be frequently mutated, leading to breast cancer development.[12] This review includes how mutations in the prohibitin gene alter regulation in carcinogenesis and tumor growth in humans.
Prohibitin is well investigated to be the negative regulator of cell cycle progression and controls E2F transcriptional factor.[10] Modifications at the time of DNA replication and transcription in the gene are known to cause mutations that eventually result in cancer. In prostate cancer which is linked to the androgen receptor (AR), overexpression of PHB represses AR-induced gene activation which helps in suppressing the growth of tumor in AR-dependent LNCaP xenografts.[13] In prostate cells, 5-alpha-reductase converts testosterone into dihydrotestosterone. AR being a ligand-activator transcription factor, when it binds to the androgen (e.g., DCT), it mediates androgen responses.[9],[11] Further, in ER-positive breast cancer, the PHB plays a significant role by activating AR leading to potential molecular targets for breast cancer treatment.[14] In the 3'-untranslated region (3'-UTR) of the prohibitin gene, mutation at position 729, i.e., single nucleotide polymorphism in the breast cancer cells, results in the formation of a variant T allele that lacks antiproliferative activity of C allele.[15],[16] This observation later concluded as women with T allele have more susceptibility toward breast cancer.[13] Moreover, both PHB1 and PH2 have shown to play roles in cancer cell proliferation, cancer cell metastasis, and cancer cell apoptosis.[16] It is important to note that apart from breast cancer, none of the somatic mutations was identified in ovary, liver, and lung cancer.[2]
| Prohibitin Gene | | |
Prohibitin is a special class of proteins and is highly conserved in nature. The human genome encodes two proteins: PHB 1 and PHB 2. They function independently as heterodimeric complexes and are found to have a significant role in transcription, cell division, and membrane metabolism and thus are key regulators in effect of cancer and other metabolic diseases.[1] Prohibitin, which is a chaperone protein, displays potency of an antiproliferative role. Studies suggest that 3'-UTR of the PHB gene encodes a functional RNA. This arrests the proliferation of the cell cycle between G1 and S phase.[15] Prohibitin gene is found to repress cell growth. This is achieved by modulating E2F transcriptional activity.[12] To add more, prohibitin also regulates transcription by remodeling chromatin molecules.[17] The dual modulating transcriptional function of prohibitin reveals its association with p53, an established tumor suppressor gene, binding to its consensus DNA site.[18],[19]
| Localization of the Gene | | |
Studies suggest that PHB1 and PHB2 localize in the nucleus, mitochondria, and cytosol of the cell [Figure 1].[20] PHB proteins depend on mitochondrial functions. Both PHB1 and PHB2 assemble at the inner membrane of mitochondria in order to form a supra macromolecular structure. This structure works as a scaffold for lipids and proteins and thus regulates mitochondrial metabolism.[21] In the nucleus, PHBs modify DNA associated enzymes, transcriptional factors, co-regulators, and receptors.[1] Whereas in cytosol, they interact with proteins associated with cytoskeletal transport and cellular signaling.[1] Studies suggest that the primary function of PHBs is restricted to mitochondria only.[22] They are expressed in high energy demanding cells which are more susceptible toward mitochondrial dysfunction. It targets the N terminus and signals for nuclear localization at the C terminus. Whereas in case of PHB1 in humans, the N terminus does not possess mitochondrial targeting sequence.[23] PHB is one of the potential substrates for Akt. Akt/protein kinase B-dependent phosphorylation of PHB1 at Thr258 leads to mitochondrial translocation of the protein.[24] This phosphorylation of PHB leads to transcriptional regulation of E2F protein and further activates Ras-Raf pathway.[25] Localization of prohibitin in the mitochondria and nucleus along with crucial binding partners is shown in [Figure 1]. | Figure 1: Localization of prohibitin in the mitochondria and nucleus along with crucial binding partners
Click here to view |
| Mutations in Prohibitin | | |
Mutations in the prohibitin gene have shown their role in tumor development. In a study, it was found that normal prohibitin was able to bind with retinoblastoma tumor suppressor protein and its family members p107 and p130, which interact with E2F family of transcriptional factors while the mutant prohibitin did not.[26] The gene location of prohibitin is 17q21, in which loss of heterozygosity was found to have a role in sporadic breast cancer and was also found to be inheritable.[27],[28] In a study in India on 105 breast cancer patients, it was found that the expression of prohibitin is different on the basis of mutation, thus proving the association of prohibitin gene with the development of cancer.[29] According to a study, it was found that prohibitin is overexpressed in papillary thyroid carcinomas bearing BRAF (V600E), in which BRAF is an oncogene.[30] The overexpression of prohibitin could be the mechanism to overcome the negative effect of the BRAF oncogene.
| Role of Prohibitin in Cancer | | |
Many studies have shown a direct relation of loss of heterozygosity at chromosome 17q21, a region found to be frequently mutated in sporadic breast cancer.[12],[27],[28],[29] A study has shown that overexpression of prohibitin is seen to have relation with prostate cancer.[31] Another study has shown overexpression of prohibitin to be directly related to prostrate cancer and bladder cancer.[32] To add more, one study exhibited the relation between loss of prohibitin and ovarian cancer.[33] Prohibitin also has binding sites for micro-RNA-27a (miR-27a), which is linked to overexpression gastric cancer[34] and also hepatocellular carcinoma.[35] The promoter region of PHB1 contains consensus binding domains for Myc oncoprotein that can lead to overexpression in different cancer types.[33],[36] PHB1 has also proved to be a tumor suppressor in hepatocytes.[37] By interacting with p53, PHB1 has also shown to inhibit proliferation of human osteosarcoma.[38] In nasopharyngeal carcinoma, PHB1 is found to be down-regulated.[39] Down-regulation of PHB1 has shown to inhibit cancer cell proliferation in esophageal squamous cell carcinoma.[40] In the hypoxic tumor microenvironment, PHB2 has been observed to contribute to hepatocellular carcinoma growth and malignancy progression.[41] Inhibition of PBH2/repressor of estrogen receptor activity (REA) transcription complex was observed in estrogen-dependent carcinomas.[42] In a study, it was noted that PHB1 is frequently overexpressed in lung cancer cells.[43] Similarly, PHB1 and PHB2 have proved their roles in several cancers, cancer cell metastasis, and cancer cell apoptosis.[9] Overall, prohibitin’s expression is not always down-regulated and at the same time is not always up-regulated while analyzing different cancer types and the gene can thus be placed in dual category, possessing anti- and pro-tumorigenic activities.[44] The expression pattern of PHB in various types of cancer is shown in [Table 1].
| Prohibitin’s Role in Oxidative Stress and Other Diseases | | |
The imbalance in the production and accumulation of reactive oxygen species in cells and tissues and body’s ability to detoxify it is known as oxidative stress.[53] It is known from previous reports that PHB1 has a function in resisting oxidative stress in various cell types. The level of PHB1 is reduced during the oxidative stress in epithelial cells of the intestine[54] and also in ex vivo lung tissue in case of hyperoxia.[44],[55] The vital link of PHB with oxidative stress is noted due to the relation between oxidative stress and the development of neurodegenerative diseases,[56],[57] such as Alzheimer’s disease (AD), Parkinson’s disease (PD), diabetes mellitus,[58] atherosclerosis and cardiovascular diseases,[59] metabolic syndrome, and skin and tumor diseases.[60],[61] In future, deeper analysis of the role of PHB in oxidative stress would open a new therapeutic window in treating various diseases.
| Therapeutic Application of Prohibitin in Cancer | | |
Prohibitin acts as a potential biomarker for tissue-based interactions of gastric cancers. This detection is carried using immunohistochemistry and real-time PCR.[53] It targets tyrosine target signaling. Once activation of insulin receptors is achieved, cytoplasmic domain modifications take place including auto-phosphorylation and dimerization. In a study involving breast cancer participants from India, the expression of prohibitin and its correlation with various clinico-pathological variables were found to be mainly significant. The same study also observed some point mutations in the breast cancer samples and mapped it to the exon 4 region.[29]
At first, PHB1 at Tyr-144 is phosphorylated by stimulation with insulin. This creates a binding site at SH2 domain which contains tyrosine phosphatase 1 (SHP1). It alters phosphorylation of Akt and glycogen synthase kinase-3β.[26],[62] Modifications by PHB1 associated with the significance of O-GlcNac are unclear. But, studies suggest that it is functionally relevant with phosphorylation at sites Tyr-114, Ser-121, Thr-258, and Tyr-259 in PHB1, which indicates its crucial role in PHB functions.[63],[64] Interestingly the exon 4 region of prohibitin contains the domain for binding retinoblastoma and E2F transcription factor.[26] These important findings indicate that prohibitin not only can be used as a biomarker but also holds potential in treating at least breast cancer. The mitochondrial inner membrane proteins OMA1 zinc metallopeptidase (OMA1) and optic atrophy-1 (OPA1) are regulated by tumor proteins p53 and prohibitins, PHB1 and PHB2 with reference to neoplastic diseases. Cancer cells rely on OMA1 and OPA1 for survival and thus confer resistance to chemotherapy.[65] In case of prostrate cancer, prohibitin along with heat shock protein 27 (HSP27) and aldehyde dehydrogenase 6A1 (ALDH6A1) acts as a tribiomarker. The trio predicts late metastatic prostate cancer.[66]
Rocaglamide is a natural anticancer drug which is shown to be directly bound to PHB1 and PHB2 and further inhibits the CRaf-MEK-ERK pathway and cancer cell proliferation. The knockdown of PHB mimics the role of rocaglamides on CRaf-MEK-ERK pathway and cell-cycle regulation. MEK/ERK pathway is the important pathway that regulates the chain of protein synthesis, which is involved in tumor cell survival and cancer progression; PHB here shows to have potential as molecular target for cancer chemotherapy.[67]
| Prohibitin Role in Other Diseases | | |
Prohibitin is found inside the mitochondria of cells, and mitochondria are responsible for providing energy for almost every biochemical and physiological reaction in our body. Mutations in PHB can induce not only cancer, but also many other diseases such as PD, AD, and diseases associated with kidney and heart [Figure 2]. Prohibitin has been linked to adipocyte as the overexpressing of prohibitin promoted adipogenesis and its knockdown resulted in enervated adipogenesis.[68],[69] In Saccharomyces cerevisiae, the disruption of prohibitin caused much decrease in the lifespan (replicative) and also resulted in the morphological change in the cells, which is a peculiar feature of aging.[70] Previous studies related to PD and AD stated that loss of PHB can deteriorate the function of neurons.[21] In addition to this, overexpression of PHB has been found to induce resistance to apoptosis and provides more susceptibility to apoptosis in case of less production of PHB. It has also been found that PHB is related to the modulation of the ATP Synthase complex[71] due to mitochondrial dysfunction.[21] Evidence shows that transglutaminase serves as the substrate for prohibitin which might help in the pathogenesis of sporadic AD, Huntington’s disease, and other neurological diseases.[21],[72] | Figure 2: Interaction of PHB gene with diseases. Mutations in PHB show various effects not only on cancer but on other diseases as well
Click here to view |
Prohibitin being a part of molecular pathways has its significance in diseases associated to heart and kidneys as well. PHB serves as a target molecule in cardio-vascular screening and can be used as a therapeutic approach toward the same.[73] In renal diseases, the mitochondrial network associated with glomerular cells regulates the function of nephrons in ultrafiltration of urine. In a mouse model, podocyte-specific PHB-2 knockout has been observed to cause glomerulosclerosis, renal failure, and death within 4–5 days.[54],[21],[74] The interaction of prohibitin with diseases is shown in [Figure 2].
| Conclusion | | |
The role of prohibitin in cancer development is not new but recent studies have noticed the activity of prohibitin in a more meaningful way. In some cases, prohibitin is known to contribute to the development or progression of cancer, whereas major studies have pointed out its activity in inhibition of cancer cells. Overall, prohibitin’s function in tumor suppression holds much more potential when compared with contradictory studies that place the gene in the pro-tumorigenic category. The protein expression analysis has also uncovered the fact that prohibitin can be used as a potential biomarker in the prognosis of cancer. Interestingly, the presence of crucial binding sites for the tumor suppressive genes such as retinoblastoma (Rb), p53, and E2F on the prohibitin’s domain exhibits the therapeutic value in terms of treatment and disease management.
Financial support and sponsorship
The grant for this project was provided by the Department of Science and Technology (DST) (Grant No.: SR/WOS-A/LS-525/2016), Government of India, New Delhi, India.
Conflicts of interest
The authors declare that there is no conflict of interest.
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[Figure 1], [Figure 2]
[Table 1]
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