CHIP-mediated degradation of transglutaminase 2 negatively regulates tumor growth and angiogenesis in renal cancer

B, Min; Park, H; S, Lee; Y, Li; Choi, Jong Myung; Jy, Lee; J, Kim; Yd, Choi; Yg, Kwon; Hw, Lee; Sc, Bae; Yun, Chae Ok; Chung, Kevin C.

doi:10.1038/onc.2015.439

Cited by 20 publications

(23 citation statements)

References 43 publications

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“…CHIP is reported to have a tumor suppressor function in renal [52], gastric [53,54], colorectal [55] and breast cancers [56,57] with an unknown mechanism. We had earlier shown that CHIP is able to restore wild-type function to mutant p53 thus causing hypoxic tumor regression [48].…”

Section: Discussionmentioning

confidence: 99%

CHIP promotes autophagy‐mediated degradation of aggregating mutant p53 in hypoxic conditions

Maan

Pati

2018

The FEBS Journal

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Tumor suppressor protein p53 aggregates in the hypoxic core of solid tumors. C terminus of Hsc70-interacting protein (CHIP) displays chaperone as well as E3 ligase activities in both stabilizing and degrading wild-type and mutant p53. In this study, we have discovered that CHIP selectively degrades aggregating mutant p53 under both normal and hypoxic conditions. Silencing of CHIP alleviates degradation of aggregating mutant p53 in both normoxia and hypoxia, but has no significant effect on the level of nonaggregating mutant p53. Although both U-box and TPR domains of CHIP are responsible for p53 degradation, the U-box domain selectively binds to aggregating mutant p53, whereas the TPR domain interacts with nonaggregating mutant p53. The degradation of mutant p53 by CHIP is shown to be via autophagy through K63-linked polyubiquitination. Both in normoxia and under physiological hypoxia, the level of aggregating mutant p53 in the presence of CHIP was reduced threefold, whereas under serum starvation, it was reduced fivefold. Interestingly, both wild-type and mutant p53 interact with and stabilize CHIP at the post-translational level, suggesting a chaperone synergy between p53 and CHIP. This finding may have strong therapeutic significance via selective degradation of oncogenic mutant p53 in regressing hypoxic tumors.

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Section: Discussionmentioning

confidence: 99%

CHIP promotes autophagy‐mediated degradation of aggregating mutant p53 in hypoxic conditions

Maan

Pati

2018

The FEBS Journal

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“…These effects are reversed by TG2 knockdown . The ubiquitination system also influences TG2 function, as TG2 level is reduced following modification by CHIP (carboxyl‐terminus of hsp70‐interacting protein), an E3 ubiquitin ligase, and CHIP knockdown is associated with elevated TG2 and aggressive cancer (Figure B). This may be a unique response in renal cancer cells, as we did not observe CHIP regulation of TG2 in squamous cell carcinoma (Eckert, unpublished).…”

Section: Tg2 In Tumor Typesmentioning

confidence: 99%

“…A, The glioma reference is . B, The renal cancer references are . C, The prostate cancer reference is …”

Section: Tg2 In Tumor Typesmentioning

confidence: 99%

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

Eckert

2019

Molecular Carcinogenesis

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Transglutaminase 2 (TG2) has emerged as a key cancer cell survival factor that drives epithelial to mesenchymal transition, angiogenesis, metastasis, inflammation, drug resistance, cancer stem cell survival and stemness, and invasion and migration. TG2 can exist in a GTP‐bound signaling‐active conformation or in a transamidase‐active conformation. The GTP bound conformation of TG2 contributes to cell survival and the transamidase conformation can contribute to cell survival or death. We present evidence suggesting that TG2 has a role in human cancer, summarize what is known about the TG2 mechanism of action in a range of cancer types, and discuss TG2 as a cancer therapy target.

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“…The peculiar biochemistry of this enzyme as well as its capacity to interact with the main proteins involved in the regulation of proteostasis suggests that TG2 plays a key role in this process. For example, among the TG2 intracellular partners, many are molecular chaperones, such as the heat‐shock proteins HSP70, HSP27, HSP90 as well as co‐chaperone from the DNAjs and the BAG families . Indeed, recent compelling evidence places TG2 within the regulation of main pathways controlling the proteome homeostasis as autophagy, proteasome and exosomes .…”

Section: Introductionmentioning

confidence: 99%

TG2 regulates the heat‐shock response by the post‐translational modification of HSF1

Rossin

Villella²,

D’Eletto

et al. 2018

EMBO Reports

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Heat-shock factor 1 (HSF1) is the master transcription factor that regulates the response to proteotoxic stress by controlling the transcription of many stress-responsive genes including the heat-shock proteins. Here, we show a novel molecular mechanism controlling the activation of HSF1. We demonstrate that transglutaminase type 2 (TG2), dependent on its protein disulphide isomerase activity, triggers the trimerization and activation of HSF1 regulating adaptation to stress and proteostasis impairment. In particular, we find that TG2 loss of function correlates with a defect in the nuclear translocation of HSF1 and in its DNA-binding ability to the HSP70 promoter. We show that the inhibition of TG2 restores the unbalance in HSF1-HSP70 pathway in cystic fibrosis (CF), a human disorder characterized by deregulation of proteostasis. The absence of TG2 leads to an increase of about 40% in CFTR function in a new experimental CF mouse model lacking TG2. Altogether, these results indicate that TG2 plays a key role in the regulation of cellular proteostasis under stressful cellular conditions through the modulation of the heat-shock response.

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CHIP-mediated degradation of transglutaminase 2 negatively regulates tumor growth and angiogenesis in renal cancer

Cited by 20 publications

References 43 publications

CHIP promotes autophagy‐mediated degradation of aggregating mutant p53 in hypoxic conditions

CHIP promotes autophagy‐mediated degradation of aggregating mutant p53 in hypoxic conditions

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

TG2 regulates the heat‐shock response by the post‐translational modification of HSF1

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