Abstract
The multifunctional enzyme transglutaminase 2 (TG2) primarily catalyzes cross-linking reactions of proteins via (γ-glutamyl) lysine bonds. Several recent findings indicate that altered regulation of intracellular TG2 levels affects renal cancer. Elevated TG2 expression is observed in renal cancer. However, the molecular mechanism underlying TG2 degradation is not completely understood. Carboxyl-terminus of Hsp70-interacting protein (CHIP) functions as an ubiquitin E3 ligase. Previous studies reveal that CHIP deficiency mice displayed a reduced life span with accelerated aging in kidney tissues. Here we show that CHIP promotes polyubiquitination of TG2 and its subsequent proteasomal degradation. In addition, TG2 upregulation contributes to enhanced kidney tumorigenesis. Furthermore, CHIP-mediated TG2 downregulation is critical for the suppression of kidney tumor growth and angiogenesis. Notably, our findings are further supported by decreased CHIP expression in human renal cancer tissues and renal cancer cells. The present work reveals that CHIP-mediated TG2 ubiquitination and proteasomal degradation represent a novel regulatory mechanism that controls intracellular TG2 levels. Alterations in this pathway result in TG2 hyperexpression and consequently contribute to renal cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Erdem S, Yegen G, Telci D, Yildiz I, Tefik T, Issever H et al. The increased transglutaminase 2 expression levels during initial tumorigenesis predict increased risk of metastasis and decreased disease-free and cancer-specific survivals in renal cell carcinoma. World J Urol 2015; 33: 1553–1560.
Ku BM, Kim DS, Kim KH, Yoo BC, Kim SH, Gong YD et al. Transglutaminase 2 inhibition found to induce p53 mediated apoptosis in renal cell carcinoma. FASEB J 2013; 27: 3487–3495.
Kim DS, Choi YB, Han BG, Park SY, Jeon Y, Kim DH et al. Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking. Oncogene 2011; 30: 4780–4790.
Ku BM, Kim SJ, Kim N, Hong D, Choi YB, Lee SH et al. Transglutaminase 2 inhibitor abrogates renal cell carcinoma in xenograft models. J Cancer Res Clin Oncol 2014; 140: 757–767.
Greenberg CS, Birckbichler PJ, Rice RH . Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J 1991; 5: 3071–3077.
Kaelin WG Jr . Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002; 2: 673–682.
Pavlovich CP, Schmidt LS . Searching for the hereditary causes of renal-cell carcinoma. Nat Rev Cancer 2004; 4: 381–393.
Wiesener MS, Munchenhagen PM, Berger I, Morgan NV, Roigas J, Schwiertz A et al. Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas. Cancer Res 2001; 61: 5215–5222.
Johnson TS, Fisher M, Haylor JL, Hau Z, Skill NJ, Jones R et al. Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease. J Am Soc Nephrol 2007; 18: 3078–3088.
Koleganova N, Piecha G, Ritz E, Schirmacher P, Muller A, Meyer HP et al. Arterial calcification in patients with chronic kidney disease. Nephrol Dial Transplant 2009; 24: 2488–2496.
Chen NX, O'Neill K, Chen X, Kiattisunthorn K, Gattone VH, Moe SM . Transglutaminase 2 accelerates vascular calcification in chronic kidney disease. Am J Nephrol 2013; 37: 191–198.
Elsasser HP, MacDonald R, Dienst M, Kern HF . Characterization of a transglutaminase expressed in human pancreatic adenocarcinoma cells. Eur J Cell Biol 1993; 61: 321–328.
Verma A, Wang H, Manavathi B, Fok JY, Mann AP, Kumar R et al. Increased expression of tissue transglutaminase in pancreatic ductal adenocarcinoma and its implications in drug resistance and metastasis. Cancer Res 2006; 66: 10525–10533.
Mehta K, Fok J, Miller FR, Koul D, Sahin AA . Prognostic significance of tissue transglutaminase in drug resistant and metastatic breast cancer. Clin Cancer Res 2004; 10: 8068–8076.
Fok JY, Ekmekcioglu S, Mehta K . Implications of tissue transglutaminase expression in malignant melanoma. Mol Cancer Ther 2006; 5: 1493–1503.
Hwang JY, Mangala LS, Fok JY, Lin YG, Merritt WM, Spannuth WA et al. Clinical and biological significance of tissue transglutaminase in ovarian carcinoma. Cancer Res 2008; 68: 5849–5858.
Park D, Choi SS, Ha KS . Transglutaminase 2: a multi-functional protein in multiple subcellular compartments. Amino Acids 2010; 39: 619–631.
Yuan L, Siegel M, Choi K, Khosla C, Miller CR, Jackson EN et al. Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy. Oncogene 2007; 26: 2563–2573.
Hidaka H, Seki N, Yoshino H, Yamasaki T, Yamada Y, Nohata N et al. Tumor suppressive microRNA-1285 regulates novel molecular targets: aberrant expression and functional significance in renal cell carcinoma. Oncotarget 2012; 3: 44–57.
Ballinger CA, Connell P, Wu Y, Hu Z, Thompson LJ, Yin LY et al. Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 1999; 19: 4535–4545.
Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Hohfeld J et al. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 2001; 3: 93–96.
Murata S, Minami Y, Minami M, Chiba T, Tanaka K . CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep 2001; 2: 1133–1138.
Meacham GC, Patterson C, Zhang W, Younger JM, Cyr DM . The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol 2001; 3: 100–105.
Muller P, Hrstka R, Coomber D, Lane DP, Vojtesek B . Chaperone-dependent stabilization and degradation of p53 mutants. Oncogene 2008; 27: 3371–3383.
Bento CF, Fernandes R, Ramalho J, Marques C, Shang F, Taylor A et al. The chaperone-dependent ubiquitin ligase CHIP targets HIF-1alpha for degradation in the presence of methylglyoxal. PLoS One 2010; 5: e15062.
Ahmed SF, Deb S, Paul I, Chatterjee A, Mandal T, Chatterjee U et al. The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation. J Biol Chem 2012; 287: 15996–16006.
Paul I, Ahmed SF, Bhowmik A, Deb S, Ghosh MK . The ubiquitin ligase CHIP regulates c-Myc stability and transcriptional activity. Oncogene 2013; 32: 1284–1295.
Xin H, Xu X, Li L, Ning H, Rong Y, Shang Y et al. CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. J Biol Chem 2005; 280: 20842–20850.
Yang M, Wang C, Zhu X, Tang S, Shi L, Cao X et al. E3 ubiquitin ligase CHIP facilitates Toll-like receptor signaling by recruiting and polyubiquitinating Src and atypical PKC{zeta}. J Exp Med 2011; 208: 2099–2112.
Wang S, Wu X, Zhang J, Chen Y, Xu J, Xia X et al. CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer. Gut 2013; 62: 496–508.
Sarkar S, Brautigan DL, Parsons SJ, Larner JM . Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells. Oncogene 2014; 33: 26–33.
Yan S, Sun X, Xiang B, Cang H, Kang X, Chen Y et al. Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90. EMBO J 2010; 29: 3773–3786.
Xu T, Zhou Q, Zhou J, Huang Y, Yan Y, Li W et al. Carboxyl terminus of Hsp70-interacting protein (CHIP) contributes to human glioma oncogenesis. Cancer Sci 2011; 102: 959–966.
Jan CI, Yu CC, Hung MC, Harn HJ, Nieh S, Lee HS et al. Tid1, CHIP and ErbB2 interactions and their prognostic implications for breast cancer patients. J Pathol 2011; 225: 424–437.
Jang KW, Lee KH, Kim SH, Jin T, Choi EY, Jeon HJ et al. Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-kappaB inactivation to regulate breast cancer cell invasion. J Cell Biochem 2011; 112: 3612–3620.
Min JN, Whaley RA, Sharpless NE, Lockyer P, Portbury AL, Patterson C . CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol Cell Biol 2008; 28: 4018–4025.
Boroughs LK, Antonyak MA, Johnson JL, Cerione RA . A unique role for heat shock protein 70 and its binding partner tissue transglutaminase in cancer cell migration. J Biol Chem 2011; 286: 37094–37107.
Zemskov EA, Mikhailenko I, Strickland DK, Belkin AM . Cell-surface transglutaminase undergoes internalization and lysosomal degradation: an essential role for LRP1. J Cell Sci 2007; 120: 3188–3199.
Filiano AJ, Bailey CD, Tucholski J, Gundemir S, Johnson GV . Transglutaminase 2 protects against ischemic insult, interacts with HIF1beta, and attenuates HIF1 signaling. FASEB J 2008; 28: 2662–2675.
Verma A, Guha S, Wang H, Fok JY, Koul D, Abbruzzese J et al. Tissue Transglutaminase regulates focal adhesion kinase/AKT activation by modulating PTEN expression in pancreatic cancer cells. Clin Cancer Res 2008; 14: 1997–2005.
Su CH, Wang CY, Lan KH, Li CP, Chao Y, Lin HC et al. Akt phosphorylation at Thr308 and Ser473 is required for CHIP-mediated ubiquitination of the kinase. Cell Signal 2011; 23: 1824–1830.
Yakubov B, Chelladurai B, Schmitt J, Emerson R, Turchi JJ, Matei D . Extracellular tissue transglutaminase activates noncanonical NF-κB signaling and promotes metastasis in ovarian cancer. Neoplasia 2013; 15: 609–619.
Wang Y, Ren F, Wang Y, Feng Y, Wang D, Jia B et al. CHIP/Stub1 functions as a tumor suppressor and represses NF-kappaB-mediated signaling in colorectal cancer. Carcinogenesis 2014; 35: 983–991.
Ai L, Kim WJ, Demircan B, Dyer LM, Bray KJ, Skehan RR et al. The transglutaminase 2 gene (TGM2), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer. Carcinogenesis 2008; 29: 510–518.
Dyer LM, Schooler KP, Ai L, Klop C, Qiu J, Robertson KD et al. The transglutaminase 2 gene is aberrantly hypermethylated in glioma. J Neurooncol 2011; 101: 429–440.
Acknowledgements
We thank SY Kim and DH Lee for providing plasmids and JJ Hwang for providing renal cancer cell line lysates. We also thank KH Chun, IK Chung and J Song for their technical assistances, critical comments and helpful discussions. This research was supported by grants from the National Research Foundation of Korea (NRF; 2014M3C7A1064545 to KCC) funded by the Ministry of Science, ICT & Future Planning (MSIP), Republic of Korea, and from the Korea Healthcare Technology R&D Project (HI14C0093 to KCC) through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. This work was supported in part by NRF grants (2015R1A2A2A01003080 and 2007-0056092 to KCC).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Min, B., Park, H., Lee, S. et al. CHIP-mediated degradation of transglutaminase 2 negatively regulates tumor growth and angiogenesis in renal cancer. Oncogene 35, 3718–3728 (2016). https://doi.org/10.1038/onc.2015.439
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2015.439
This article is cited by
-
CHIP-mediated CIB1 ubiquitination regulated epithelial–mesenchymal transition and tumor metastasis in lung adenocarcinoma
Cell Death & Differentiation (2021)
-
Covalent ISG15 conjugation to CHIP promotes its ubiquitin E3 ligase activity and inhibits lung cancer cell growth in response to type I interferon
Cell Death & Disease (2018)
-
Transglutaminase-2: evolution from pedestrian protein to a promising therapeutic target
Amino Acids (2017)