Cancer Studies and Molecular Medicine

Open journal

ISSN 2377-1518

The Emerging Role of p27 in Development of Diseases

Qiwei Yang* and Ayman Al-Hendy

Qiwei Yang, PhD

Research Associate Professor, Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, IL 60612, USA Tel. 312-996-5689; E-mail: qiwei@uic.edu

INTRODUCTION

The cell cycle regulation and tumor suppressor p27 encoded by CDKN1B plays a key role in many cellular events.1,2,3 p27 is a member of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors, which functions to negatively regulate cell cycle progression at the G1/S boundary in response to antiproliferative stimuli. In addition, numerous p27 functions, not related to CDK inhibition, have been described. For instance, cytosolic p27 plays a role in the regulation of cytoskeleton assembly/disassembly, therefore, regulates the cell morphology and movement. In addition, p27 is involved in apoptosis and autophagy modulation.4,5,6

Mutations, abnormal expression and mislocalization of p27 have been found in many diseases suggesting the important role of p27 in the pathogenesis of diseases. Human p27 gene (CDKN1B) was cloned in 19947 and mapped to chromosome 12p13. Later on, p27 mutations were discovered in several types of human cancers including breast cancer, sporadic parathyroid adenomas, endocrine neoplasia, small intestine neuroendocrine tumors.2,8,9,10,11,12,13,14

Several types of tumors show decreased expression of p27, including breast, colon, esophageal carcinomas, head and neck cancers, hematological tumors lung, prostate, melanomas and ovarian tumors.1,15 The decreased expression of p27 is due to increased proteasome-mediated protein degradation, correlates with poor prognosis of patients. Several other studies demonstrate that a decrease in the expression levels of p27 protein contributes to tumor development by increasing in CDK activity and cell proliferation.15,16,17

In addition, an increased body of evidence demonstrates that mislocalization of p27 contributes to the development of aggressive phenotype and anticancer therapy resistance. p27 levels and subcellular localization are catalyzed by different kinases that modulate degradation and nuclear-cytoplasmic shuttling. In endometrial carcinoma cell lines, p27 is low and/or predominantly cytoplasmic p27 phosphorylation at T157 by AKT (protein kinase B). Treatment with an AKT inhibitor rescues the mislocalization of p27 to the cytoplasm in endometrial carcinoma cells.18 The mislocalization of p27 has also been identified in other types of cancers,19,20,21,22 suggesting that sequestration of p27 in the cytoplasm might be an alternative way to inactivate p27-associated inhibitory activity in cancers.

p27 AND RISK OF DISEASES

Reduced expression and mislocalization of p27 have been identified as an early event in some types of diseases. A study by McCampbell et al demonstrates that loss of p27 expression is an early event in the progression of endometrial carcinoma in the setting of obesity. p27 expression is severely reduced and/or mislocalized to the cytoplasm in histologically “normal” endometrial glands and endometrial complex hyperplasia with atypia from obese women (CAH) as compared to normal weight women. In luteal phase endometrium, p27 expression is high and primarily nuclear. In contrast, in the majority of endometrial CAH, p27 expression is severely reduced or absent in >70% of these early lesions, and is harshly reduced or absent in 89% of primary endometrial carcinoma. These data indicate that loss of p27 is retained as a feature of early (CAH) and neoplastic endometrial lesions arising in the setting of obesity. 18 Similar findings are observed in other types of human cancers.1,23 p27 is reduced in premalignant and non-invasive cancerous lesions, including ductal carcinoma in situ of the breast. The reduced p27 expression is prognostic for subsequent development of oral squamous carcinoma. In addition, in benign prostatic hypertrophy and low malignant potential of ovarian tumors, the p27 expression levels are decreased compared to normal tissues.

p27 AS A PREDICTOR OF TREATMENT RESPONSES

For animal study, Eker rats carrying a defect in the Tsc2 tumor suppressor gene are a genetically-defined model for endometrial hyperplasia that processes to endometrial carcinoma by 16 months of age.18 At the early stage of this model, appearing “pre-hyperplastic” glands with activated mTORC1 signaling correlate with loss of the wild-type Tsc2 allele. Early life exposure to xenoestrogen accelerates the development of endometrial hyperplasia in adult female rats.24 Similar to human disease, loss of p27 occurs early in association with the development of obesity-associated endometrial hyperplasia. The energy balance intervention study by McCampbell et al demonstrates that caloric restriction is capable of reducing weight, providing a favorable to leptin/adiponectin ratio, and decreasing the circulating insulin levels in response to early life exposure to genistein. Importantly, caloric restriction also significantly decreases hyperplasia incidence with increased p27 expression levels and relocalization of p27 to the nucleus.18

In human, the effect of chemotherapy can also be predicated according to the expression levels of p27 in some types of cancers. For instance, in non-small cell lung cancer25 and ovarian cancers,26 decreased expression of p27 correlates with reduced survival in response to platinum-based chemotherapy. In breast cancer,27 decreased expression of p27 is associated with poor outcome after adjuvant chemotherapy. In head and neck squamous cell carcinomas,28 p27 expression serves as a significant predictor of chemotherapy response in multivariate analysis.

FUTURE DIRECTIONS

Although progresses have been made to understand the role of p27 in the pathogenesis of diseases, there remains a gap in our knowledge regarding the abnormal expression and subcellular localization of p27, which contribute to the pathogenies of varied diseases. How these events link to the processes of abnormal cell cycle and development of diseases related to the network of signaling pathways and epigenome? What is the role of p27 in favorable and unfavorable effects of chemotherapy? Also, more preclinical studies are needed to determine the effect of treatments in varied types of cancers and diseases. For instance, the energy balance intervention study shows a potent inhibitory effect on hyperplasia incidence in Eker rat model. In addition to endometrial hyperplasia, Eker rats are also a genetically-defined model for the development of uterine fibroids.29,30 Does this dietary intervention also work for uterine fibroids through the same mechanism? Further understanding the mechanism and role of p27 may lead to the development of novel treatment options against many challenging diseases.

ACKNOWLEDGEMENT

This study was supported in part by the National Institutes of Health grant: R01 ES 028615-01.

CONFLICTS OF INTEREST

The authors report no conflicts of interest with this work.

1. Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: Prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008; 8(4): 253-267. doi: 10.1038/nrc2347

2. Bencivenga D, Caldarelli I, Stampone E, et al. p27(Kip1) and human cancers: A reappraisal of a still enigmatic protein. Cancer Lett. 2017; 403: 354-365. doi: 10.1016/j.canlet.2017.06.031

3. Wander SA, Zhao D, Slingerland JM. p27: A barometer of signaling deregulation and potential predictor of response to targeted therapies. Clin Cancer Res. 2011; 17(1): 12-18. doi: 10.1158/1078- 0432.CCR-10-0752

4. Jia W, He M-X, McLeod IX, Guo J, Ji D, He Y-W. Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1. Autophagy. 2015; 11(12): 2335-2345. doi: 10.1080/15548627.2015.1110666

5. Sun X, Momen A, Wu J, et al. p27 protein protects metabolically stressed cardiomyocytes from apoptosis by promoting autophagy. J Biol Chem. 2014; 289(24):16924-16935. doi: 10.1074/jbc.M113.542795

6. Levkau B, Koyama H, Raines EW, et al. Cleavage of p21Cip1/ Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. Mol Cell. 1998; 1(4): 553-563. doi: 10.1016/s1097-2765(00)80055-6

7. Polyak K, Lee MH, Erdjument-Bromage H, et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994; 78(1): 59- 66. doi: 10.1016/0092-8674(94)90572-x

8. Occhi G, Regazzo D, Trivellin G, et al. A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLoS Genet. 2013; 9(3): e1003350. doi: 10.1371/journal.pgen.1003350

9. Costa-Guda J, Marinoni I, Molatore S, Pellegata NS, Arnold A Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. J Clin Endocrinol Metab. 2011; 96(4): E701-E706. doi: 10.1210/jc.2010-1338

10. Dietrich S, HĂĽllein J, Lee SC, et al. Recurrent CDKN1B (p27) mutations in hairy cell leukemia. Blood. 2015; 126(8): 1005-1008. doi: 10.1182/blood-2015-04-643361

11. Stephens PJ, Tarpey PS, Davies H, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012; 486(7403): 400-404. doi: 10.1038/nature11017

12. Maxwell JE, Sherman SK, Li G, et al. Somatic alterations of CDKN1B are associated with small bowel neuroendocrine tumors. Cancer Genet. 2015; pii: S2210-S7762(15): 00184-00192. doi: 10.1016/j.cancergen.2015.08.003

13. Crona J, Gustavsson T, Norlén O, et al. Somatic mutations and genetic heterogeneity at the CDKN1B locus in small intestinal neuroendocrine tumors. Ann Surg Oncol. 2015; 22 Suppl 3: S1428- S1435. doi: 10.1245/s10434-014-4351-9

14. Francis JM, Kiezun A, Ramos AH, et al. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet. 2013; 45(12): 1483-1486. doi: 10.1038/ng.2821

15. Viglietto G, Motti ML, Fusco A. Understanding p27(kip1) deregulation in cancer: Down-regulation or mislocalization. Cell Cycle. 2002; 1(6): 394-400. doi: 10.4161/cc.1.6.263

16. Masciullo V, Sgambato A, Pacilio C, et al. Frequent loss of expression of the cyclin-dependent kinase inhibitor p27 in epithelial ovarian cancer. Cancer Res. 1999; 59(15): 3790-3794. https://pubmed.ncbi.nlm.nih.gov/10446997/

17. Loda M, Cukor B, Tam SW, et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997; 3(2): 231-234. doi: 10.1038/nm0297-231

18. McCampbell AS, Mittelstadt ML, Dere R, et al. Loss of p27 associated with risk for endometrial carcinoma arising in the setting of obesity. Curr Mol Med. 2016; 16(3): 252-265. doi: 10.2174/1566 524016666160225153307

19. Singh SP, Lipman J, Goldman H, et al. Loss or altered subcellular localization of p27 in Barrett’s associated adenocarcinoma. Cancer Res. 1998; 58(8): 1730-1735. https://pubmed.ncbi.nlm.nih.gov/9563491/

20. Sgambato A, Ratto C, Faraglia B, et al. Reduced expression and altered subcellular localization of the cyclin-dependent kinase inhibitor p27(Kip1) in human colon cancer. Mol Carcinog. 1999; 26(3): 172-179. doi: 10.1002/(SICI)1098-2744(199911)26:33.0.CO;2-8

21. Shehata MA, Nosseir HR, Nagy HM, Farouk G. Cyclin dependent kinase inhibitor p27(kip1) expression and subcellular localization in relation to cell proliferation in hepatocellualr carcinoma. Egypt J Immunol. 2006; 13(1): 115-130. https://pubmed.ncbi.nlm.nih.gov/17974156/

22. Viglietto G, Motti ML, Bruni P, et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med. 2002; 8(10): 1136-1144. doi: 10.1038/nm762

23. Catzavelos C, Bhattacharya N, Ung YC, et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med. 1997; 3(2): 227-230. https://pubmed.ncbi.nlm.nih.gov/9018244/

24. McCampbell AS, Walker CL, Broaddus RR, Cook JD, Davies PJ. Developmental reprogramming of IGF signaling and susceptibility to endometrial hyperplasia in the rat. Lab Invest. 2008; 88(6): 615-626. doi: 10.1038/labinvest.2008.29

25. Oshita F, Kameda Y, Nishio K, et al. Increased expression levels of cyclin-dependent kinase inhibitor p27 correlate with good responses to platinum-based chemotherapy in non-small cell lung cancer. Oncol Rep. 2000; 7(3): 491-495. doi: 10.3892/or.7.3.491

26. Korkolopoulou P1, Vassilopoulos I, Konstantinidou AE, et al. The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients. Gynecol Oncol. 2002; 85(3): 404-414. doi: 10.1006/gyno.2002.6627

27. Han S, Park K, Kim HY, et al. Reduced expression of p27Kip1 protein is associated with poor clinical outcome of breast cancer patients treated with systemic chemotherapy and is linked to cell proliferation and differentiation. Breast Cancer Res Treat. 1999; 55(2): 161-167. doi: 10.1023/a:1006258222233

28. Moreno-Galindo C, Hermsen M, GarcĂ­a-Pedrero JM, et al. p27 and BCL2 expression predicts response to chemotherapy in head and neck squamous cell carcinomas. Oral Oncol. 2014; 50(2): 128- 134. doi: 10.1016/j.oraloncology.2013.10.018

29. Cook JD, Davis BJ, Cai SL, Barrett JC, Conti CJ, Walker CL. Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance. Proc Natl Acad Sci U S A. 2005; 102(24): 8644-8649. doi: 10.1073/pnas.0503218102

30. Mas A, Stone L, O’Connor PM. Developmental exposure to endocrine disruptors expands murine myometrial stem cell compartment as a prerequisite to leiomyoma tumorigenesis. stem cells. 2017; 35(3): 666-678. doi: 10.1002/stem.2519

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