Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

Wu, Xiaowei; Luo, Qingyu; Liu, Zhihua

doi:10.1038/s41419-020-02760-y

Cited by 53 publications

(45 citation statements)

References 151 publications

(210 reference statements)

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“…MCL1 is highly expressed in a variety of human cancer and is often related to chemotherapeutic resistance and relapse [ 34 ]. E3 ubiquitin ligases (Mule, SCF β-TrCP , SCF FBW7 , TRIM17, APC/C Cdc20 , and FBXO4) and deubiquitinases (USP9X, Ku70, USP13, JOSD1, and DUB3) work together to balance MCL1 stability, which has an important role in the chemoresistance of cancer cells [ 35 , 36 ]. Our finding that that ASB17 promoted the ubiquitylation of MCL1 and degraded it might provide a potential therapeutic option.…”

Section: Discussionmentioning

confidence: 99%

E3 Ubiquitin Ligase ASB17 Promotes Apoptosis by Ubiquitylating and Degrading BCLW and MCL1

Yang

Wan

et al. 2021

Biology

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Apoptosis is a very important process of cell death controlled by multiple genes during which cells undergo certain events before dying. Apoptosis helps to clean the unnecessary cells and has critical physiological significance. Altered apoptosis results in a disorder of cell death and is associated with many diseases such as neurodegenerative diseases and cancers. Here, we reported that the ankyrin repeat and SOCS box protein 17 (ASB17) was mainly expressed in the testis and promoted apoptosis both in vivo and in vitro. Analyzing ASB17-deficient mice generated by using the CRISPR/Cas9 system, we demonstrated that ASB17 deficiency resulted in the reduction of apoptosis in spermatogenic cells, but it did not affect the development of spermatozoa or normal fertility. Next, in an in vivo model, ASB17 deficiency prevented the apoptosis of spermatogonia induced by etoposide in male mice. We noted that ASB17 promoted apoptosis in a caspase-dependent manner in vitro. Moreover, ASB17 interacted with the members of the BCL2 family, including BCL2, BCLX, BCLW, and MCL1. Interestingly, ASB17 specifically degraded the two anti-apoptotic factors, BCLW and MCL1, in a ubiquitylation-dependent fashion. Collectively, our findings suggested that ASB17 acted as a distinct positive regulator of cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

E3 Ubiquitin Ligase ASB17 Promotes Apoptosis by Ubiquitylating and Degrading BCLW and MCL1

Yang

Wan

et al. 2021

Biology

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“…Its ubiquitination, that targets it for proteasomal degradation, allows for rapid removal of MCL1 and initiation of cell death, in response to various cellular events [ 23 ]. Several E3 ubiquitin-ligases have been identified for MCL1 [ 94 , 95 ], including TRIM17. Indeed, we have shown TRIM17 to be an E3 ubiquitin-ligase for MCL1 in neurons [ 72 ].…”

Section: Cellular Functions Of Trim17mentioning

confidence: 99%

To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death

Basu-Shrivastava

Kozoriz

Desagher

et al. 2021

Cells

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TRIM17 is a member of the TRIM family, a large class of RING-containing E3 ubiquitin-ligases. It is expressed at low levels in adult tissues, except in testis and in some brain regions. However, it can be highly induced in stress conditions which makes it a putative stress sensor required for the triggering of key cellular responses. As most TRIM members, TRIM17 can act as an E3 ubiquitin-ligase and promote the degradation by the proteasome of substrates such as the antiapoptotic protein MCL1. Intriguingly, TRIM17 can also prevent the ubiquitination of other proteins and stabilize them, by binding to other TRIM proteins and inhibiting their E3 ubiquitin-ligase activity. This duality of action confers several pivotal roles to TRIM17 in crucial cellular processes such as apoptosis, autophagy or cell division, but also in pathological conditions as diverse as Parkinson’s disease or cancer. Here, in addition to recent data that endorse this duality, we review what is currently known from public databases and the literature about TRIM17 gene regulation and expression, TRIM17 protein structure and interactions, as well as its involvement in cell physiology and human disorders.

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“…Myeloid cell leukemia 1 (MCL-1), an antiapoptotic B-cell lymphoma 2 (Bcl-2) family protein, blocks intrinsic pathway-initiated apoptosis by interfering with BAX–BAK interaction. The increased expression of MCL-1 has been observed in human cancers and has been associated with the induction of resistance to chemo-radiotherapy and targeting therapy [ 32 , 33 , 34 ]. The inhibition of MCL-1 expression has been indicated to reverse regorafenib resistance in CRC cells through the restoration of regorafenib-induced apoptosis [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

Chen

Hsu

Chen

et al. 2021

Cancers

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While regorafenib was approved for the treatment of advanced HCC in 2017, with a partial response and survival benefit; other combination agents to facilitate the efficacy of regorafenib still need to be explored. Magnolol is a potential natural anti-tumor compound for many types of cancers. Combination indexes calculated on the basis of both in vitro and in vivo models have indicated a synergistic effect of the combination of regorafenib and magnolol. The overexpression of the VEGF-A protein significantly diminished regorafenib’s inhibition of cell viability, while the transient knockdown of VEGF-A by siRNA effectively sensitized HCC cells to regorafenib. In addition, the inhibition of MCL-1 by siRNA combined with regorafenib allowed for a significantly greater inhibition of cell growth, compared to regorafenib alone. A lower protein expression level for VEGF-A and MCL-1 was found for the combination treatment of HCC in vitro and in vivo. A superior metastasis inhibition was also found in the combination group, as compared to the single-treatment groups, using a transwell assay, wound healing assay, and Western blotting. The caspase-dependent and -independent and DNA damage effects, as determined by flow cytometry and a comet assay, were increased by the combination therapy. Taken together, magnolol sensitized HCC to regorafenib, which was correlated with the reduction of VEGF-A and MCL-1 and the induction of apoptosis.

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Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

Cited by 53 publications

References 151 publications

E3 Ubiquitin Ligase ASB17 Promotes Apoptosis by Ubiquitylating and Degrading BCLW and MCL1

E3 Ubiquitin Ligase ASB17 Promotes Apoptosis by Ubiquitylating and Degrading BCLW and MCL1

To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

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