Overexpression of CUL4B is a novel predictor of prognosis for endometrial adenocarcinoma

Purpose: It is reported that Cullin 4B (CUL4B) plays a crucial role in many physiological process. This study for the first time investigated the role of CUL4B in endometrioid adenocarcinoma (EAC). Materials and Methods: CUL4B mRNA and protein expression in EAC tissues and normal endometrial (NE) tissues were examined by real-time PCR and immunohistochemistry. The authors also explored the correlation between CUL4B protein expression and clinicopathological characteristics. Moreover, univariate and multivariate Cox regression analyses and Kaplan-Meier survival analyses were performed to investigate the association between TRIM62 expression and EAC patients’ prognosis. Results: CUL4B was markedly overexpressed in EAC at both mRNA and protein levels. Immunohistochemistry assays showed that high CUL4B expression was significantly correlated with FIGO stage (p = 0.008) and histological grade (p = 0.002). Univariate and multivariate analyses revealed that CUL4B was an independent poor prognostic factor for overall and disease-free survival of EAC patients (p < 0.05). Furthermore, survival analyses displayed that patients with high CUL4B expression had poor prognosis. Conclusion: The present results demonstrated that elevated CUL4B was associated with poor outcomes of patients with EAC. CUL4B may serve as a novel prognostic marker and therapeutic target for EAC.

CUL4B; Endometrial carcinoma; Prognosis

[1] Amant F., Moerman P., Neven P., Timmerman D., Van Limbergen E., Vergote I.: “Endometrial cancer”. Lancet, 2005, 366, 491.

[2] Jemal A., Murray T., Ward E., Samuels A., Tiwari R.C., Ghafoor A., et al.: “Cancer statistics, 2005”. CA Cancer J. Clin., 2005, 55, 10.

[3] De Vivo I., Prescott J., Setiawan V.W., Olson S.H., Wentzensen N., Attia J., et al.: “Genome-wide association study of endometrial cancer in E2C2”. Hum. Genet., 2014, 133, 211.

[4] Tangjitgamol S., Anderson B.O., See H.T., Lertbutsayanukul C., Sirisabya N., Manchana T., et al.: “Management of endometrial cancer in Asia: consensus statement from the Asian Oncology Summit 2009”. Lancet Oncol., 2009, 10, 1119.

[5] Madison T., Schottenfeld D., James S.A., Schwartz A.G., Gruber S.B.: “Endometrial cancer: socioeconomic status and racial/ethnic differences in stage at diagnosis, treatment, and survival”. Am. J. Public Health, 2004, 94, 2104.

[6] Hill H.A., Eley J.W., Harlan L.C., Greenberg R.S., Barrett R.N., Chen V.W.: “Racial differences in endometrial cancer survival: the black/white cancer survival study”. Obstet Gynecol., 1996, 88, 919.

[7] Nahleh Z.A.: “Hormonal therapy for male breast cancer: A different approach for a different disease”. Cancer Treat Rev., 2006, 32, 101.

[8] Schouten L.J., Goldbohm R.A., van den Brandt P.A.: “Anthropometry, physical activity, and endometrial cancer risk: results from the Netherlands Cohort Study”. J. Natl. Cancer Inst., 2004, 96, 1635.

[9] Greenlee R.T., Murray T., Bolden S., Wingo P.A.: “Cancer statistics, 2000”. CA Cancer J. Clin., 2000, 50, 7.

[10] Hershko A., Ciechanover A., Heller H., Haas A.L., Rose I.A.: “Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis”. Proc. Natl. Acad. Sci. U S A, 1980, 77, 1783.

[11] Ciechanover A., Heller H., Elias S., Haas A.L., Hershko A.: “ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation”. Proc. Natl. Acad. Sci. U S A, 1980, 77, 1365.

[12] Ciehanover A., Hod Y., Hershko A.: “A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes”. Biochem. Biophys. Res. Commun., 1978, 81, 1100.

[13] Min K.W., Hwang J.W., Lee J.S., Park Y., Tamura T.A., Yoon J.B.: TIP120A associates with cullins and modulates ubiquitin ligase activity” J. Biol. Chem., 2003, 278, 15905.

[14] Wilkinson K.D.: “Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome”. Semin. Cell. Dev. Biol., 2000, 11, 141.

[15] Sarikas A., Hartmann T., Pan Z.Q.: “The cullin protein family”. Genome Biol., 2011, 12,220.

[16] Jackson S., Xiong Y.: “CRL4s: the CUL4-RING E3 ubiquitin ligases”. Trends Biochem. Sci., 2009, 34, 562.

[17] Hu H., Yang Y., Ji Q., Zhao W., Jiang B., Liu R., et al.: “CRL4B catalyzes H2AK119 monoubiquitination and coordinates with PRC2 to promote tumorigenesis”. Cancer Cell., 2012, 22, 781.

[18] Jiang T., Tang H.M., Wu Z.H., Chen J., Lu S., Zhou C.Z., et al.: “Cullin 4B is a novel prognostic marker that correlates with colon cancer progression and pathogenesis”. Med. Oncol., 2013, 30, 534.

[19] Huang P., Qiu J., Li B., Hong J., Lu C., Wang L., et al.: “Role of Sox2 and Oct4 in predicting survival of hepatocellular carcinoma patients after hepatectomy”. Clin. Biochem., 2011, 44, 582.

[20] Schmittgen T.D., Livak K.J.: “Analyzing real-time PCR data by the comparative C(T) method”. Nat. Protoc., 2008, 3, 1101.

[21] Birner P., Schindl M., Obermair A., Plank C., Breitenecker G., Oberhuber G.: “Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer”. Cancer Res., 2000, 60, 4693.

[22] Kudo Y., Guardavaccaro D., Santamaria P.G., Koyama-Nasu R., Latres E., Bronson R., et al.: “Role of F-box protein betaTrcp1 in mammary gland development and tumorigenesis”. Mol. Cell. Biol., 2004, 24, 8184.

[23] King R.W., Deshaies R.J., Peters J.M., Kirschner M.W.: “How proteolysis drives the cell cycle”. Science, 1996, 274, 1652.

[24] Sharma P., Nag A.: “CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases”. Open Biol., 2014, 4, 130217.

[25] Wang Y., Ma G., Wang Q., Wen M., Xu Y., He X., et al.: “Involvement of CUL4A in regulation of multidrug resistance to P-gp substrate drugs in breast cancer cells”. Molecules, 2013, 19, 159.

[26] Tarpey PS, Raymond FL, O’Meara S, Edkins S, Teague J, Butler A, et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am. J. Hum. Genet., 2007, 80, 345.

[27] Guerrero-Santoro J., Kapetanaki M.G., Hsieh C.L., Gorbachinsky I.,“Levine A.S., Rapić-Otrin V.: “The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A”. Cancer Res., 2008, 68, 5014.

[28] Perkins N.D.: “Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway”. Oncogene, 2006, 25, 6717.

[29] Hao B., Zheng N., Schulman B.A., Wu G., Miller J.J., Pagano M., et al.: “Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase”. Mol. Cell., 2005, 20, 9.

[30] Fuchs S.Y.: “The role of ubiquitin-proteasome pathway in oncogenic signaling”. Cancer Biol. Ther., 2002, 1, 337.