NAC-1, a Potential Stem Cell Pluripotency Factor, Contributes to Paclitaxel Resistance in Ovarian Cancer Through Inactivating Gadd45 Pathway

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2009 Mar 24

PMID 19305429

Citations 46

Authors

N Jinawath

C Vasoontara

K-L Yap

M M Thiaville

K Nakayama

T-L Wang

I-M Shih

Affiliations

Soon will be listed here.

Abstract

Nucleus accumbens-1 (Nac1 or NAC-1) belongs to the BTB/POZ (Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad complex) transcription factor family and is a novel protein that potentially participates in self-renewal and pluripotency in embryonic stem cells. In human cancer, NAC-1 is upregulated in several types of neoplasms, but particularly in recurrent chemoresistant ovarian carcinomas, suggesting a biological role for NAC-1 in the development of drug resistance in ovarian cancer. We have assessed this possibility and shown a correlation between NAC-1 expression and ex vivo paclitaxel resistance in ovarian serous carcinoma tissues and cell lines. We found that expression of Gadd45-gamma-interacting protein 1 (Gadd45gip1), a downstream target negatively regulated by NAC-1, was reduced in paclitaxel-resistant cells. Ectopic expression of NAC-1 or knockdown of Gadd45gip1 conferred paclitaxel resistance, whereas NAC-1 knockdown or ectopic expression of Gadd45gip1 increased paclitaxel sensitivity. Furthermore, silencing NAC-1 expression or disrupting NAC-1 homodimerization by a dominant negative NAC-1 protein that contained only the BTB/POZ domain induced the expression of Gadd45gamma, which interacted with Gadd45gip1. Reducing Gadd45gamma expression by small hairpin RNAs partially enhanced paclitaxel resistance. Thus, this study provides new evidence that NAC-1 upregulation and homodimerization contribute to tumor recurrence by equipping ovarian cancer cells with the paclitaxel-resistant phenotype through negative regulation of the Gadd45 pathway.

Citing Articles

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer.

Ngule C, Shi R, Ren X, Jia H, Oyelami F, Li D Mol Cancer. 2024; 23(1):188.

PMID: 39243032 PMC: 11378519. DOI: 10.1186/s12943-024-02102-y.

NIPBL::NACC1 Fusion Hepatic Carcinoma.

Hissong E, Al Assaad M, Bal M, Reed K, Fornelli A, Levine M Am J Surg Pathol. 2023; 48(2):183-193.

PMID: 38047392 PMC: 11238093. DOI: 10.1097/PAS.0000000000002159.

Solid-Tubulocystic carcinoma: A new variant of intrahepatic cholangiocarcinoma.

Gonzalez I, Luo W, Zhang X World J Hepatol. 2023; 15(7):897-903.

PMID: 37547028 PMC: 10401414. DOI: 10.4254/wjh.v15.i7.897.

Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion.

Ren Y, Kumar A, Das J, Peng H, Wang L, Balllard D J Immunother Cancer. 2022; 10(9).

PMID: 36150745 PMC: 9511653. DOI: 10.1136/jitc-2022-004856.

Expression of NAC1 Restrains the Memory Formation of CD8 T Cells during Viral Infection.

Wang L, Kumar A, Das J, Ren Y, Peng H, Ballard D Viruses. 2022; 14(8).

PMID: 36016335 PMC: 9414488. DOI: 10.3390/v14081713.

References

Tang G, Minemoto Y, Dibling B, Purcell N, Li Z, Karin M . Inhibition of JNK activation through NF-kappaB target genes. Nature. 2001; 414(6861):313-7. DOI: 10.1038/35104568. View

Duan Z, Foster R, Bell D, Mahoney J, Wolak K, Vaidya A . Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res. 2006; 12(17):5055-63. DOI: 10.1158/1078-0432.CCR-06-0861. View

Chung H, Yi Y, Jung N, Kim D, Suh J, Kim H . CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle. J Biol Chem. 2003; 278(30):28079-88. DOI: 10.1074/jbc.M212835200. View

Zhang S, Balch C, Chan M, Lai H, Matei D, Schilder J . Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008; 68(11):4311-20. PMC: 2553722. DOI: 10.1158/0008-5472.CAN-08-0364. View

Mackler S, Korutla L, Cha X, Koebbe M, Fournier K, Bowers M . NAC-1 is a brain POZ/BTB protein that can prevent cocaine-induced sensitization in the rat. J Neurosci. 2000; 20(16):6210-7. PMC: 6772573. View

Dimova I, Raitcheva S, Dimitrov R, Doganov N, Toncheva D . Correlations between c-myc gene copy-number and clinicopathological parameters of ovarian tumours. Eur J Cancer. 2006; 42(5):674-9. DOI: 10.1016/j.ejca.2005.11.022. View

Nakayama K, Nakayama N, Wang T, Shih I . NAC-1 controls cell growth and survival by repressing transcription of Gadd45GIP1, a candidate tumor suppressor. Cancer Res. 2007; 67(17):8058-64. DOI: 10.1158/0008-5472.CAN-07-1357. View

Baker V, Borst M, Dixon D, Hatch K, SHINGLETON H, Miller D . c-myc amplification in ovarian cancer. Gynecol Oncol. 1990; 38(3):340-2. DOI: 10.1016/0090-8258(90)90069-w. View

Abeysinghe H, Cedrone E, Tyan T, Xu J, Wang N . Amplification of C-MYC as the origin of the homogeneous staining region in ovarian carcinoma detected by micro-FISH. Cancer Genet Cytogenet. 1999; 114(2):136-43. DOI: 10.1016/s0165-4608(99)00064-3. View

10.

Yusuf R, Duan Z, Lamendola D, Penson R, Seiden M . Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets. 2003; 3(1):1-19. DOI: 10.2174/1568009033333754. View

11.

Abhiman S, Iyer L, Aravind L . BEN: a novel domain in chromatin factors and DNA viral proteins. Bioinformatics. 2008; 24(4):458-61. PMC: 2477736. DOI: 10.1093/bioinformatics/btn007. View

12.

Qiu W, Zhou B, Zou H, Liu X, Chu P, Lopez R . Hypermethylation of growth arrest DNA damage-inducible gene 45 beta promoter in human hepatocellular carcinoma. Am J Pathol. 2004; 165(5):1689-99. PMC: 1618679. DOI: 10.1016/s0002-9440(10)63425-6. View

13.

Duan Z, Duan Y, Lamendola D, Yusuf R, Naeem R, Penson R . Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicin-resistant human cancer cell lines. Clin Cancer Res. 2003; 9(7):2778-85. View

14.

Yeasmin S, Nakayama K, Ishibashi M, Katagiri A, Iida K, Purwana I . Expression of the bric-a-brac tramtrack broad complex protein NAC-1 in cervical carcinomas seems to correlate with poorer prognosis. Clin Cancer Res. 2008; 14(6):1686-91. DOI: 10.1158/1078-0432.CCR-07-4085. View

15.

Nakayama K, Nakayama N, Davidson B, Sheu J, Jinawath N, Santillan A . A BTB/POZ protein, NAC-1, is related to tumor recurrence and is essential for tumor growth and survival. Proc Natl Acad Sci U S A. 2006; 103(49):18739-44. PMC: 1693732. DOI: 10.1073/pnas.0604083103. View

16.

Mabuchi S, Ohmichi M, Nishio Y, Hayasaka T, Kimura A, Ohta T . Inhibition of NFkappaB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models. J Biol Chem. 2004; 279(22):23477-85. DOI: 10.1074/jbc.M313709200. View

17.

Kim J, Chu J, Shen X, Wang J, Orkin S . An extended transcriptional network for pluripotency of embryonic stem cells. Cell. 2008; 132(6):1049-61. PMC: 3837340. DOI: 10.1016/j.cell.2008.02.039. View

18.

Liu G, Wang S, Wang B, Kong B . Inhibition of nuclear factor-kappaB by an antioxidant enhances paclitaxel sensitivity in ovarian carcinoma cell line. Int J Gynecol Cancer. 2006; 16(5):1777-82. DOI: 10.1111/j.1525-1438.2006.00652.x. View

19.

Ishibashi M, Nakayama K, Yeasmin S, Katagiri A, Iida K, Nakayama N . A BTB/POZ gene, NAC-1, a tumor recurrence-associated gene, as a potential target for Taxol resistance in ovarian cancer. Clin Cancer Res. 2008; 14(10):3149-55. DOI: 10.1158/1078-0432.CCR-07-4358. View

20.

Boyer L, Lee T, Cole M, Johnstone S, Levine S, Zucker J . Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005; 122(6):947-56. PMC: 3006442. DOI: 10.1016/j.cell.2005.08.020. View