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Review
. 2018 Apr:44:92-102.
doi: 10.1016/j.cellsig.2018.01.009. Epub 2018 Jan 10.

Protein neddylation and its alterations in human cancers for targeted therapy

Lisha Zhou  1 , Wenjuan Zhang  2 , Yi Sun  3 , Lijun Jia  4
Affiliations
Review

Protein neddylation and its alterations in human cancers for targeted therapy

Lisha Zhou et al. Cell Signal. 2018 Apr.

Abstract

Neddylation, a post-translational modification that conjugates an ubiquitin-like protein NEDD8 to substrate proteins, is an important biochemical process that regulates protein function. The best-characterized substrates of neddylation are the cullin subunits of Cullin-RING ligases (CRLs), which, as the largest family of E3 ubiquitin ligases, control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins. Recently, increasing pieces of experimental evidence strongly indicate that the process of protein neddylation modification is elevated in multiple human cancers, providing sound rationale for its targeting as an attractive anticancer therapeutic strategy. Indeed, neddylation inactivation by MLN4924 (also known as pevonedistat), a small molecule inhibitor of E1 NEDD8-activating enzyme currently in phase I/II clinical trials, exerts significant anticancer effects by inducing cell cycle arrest, apoptosis, senescence and autophagy in a cell-type and context dependent manner. Here, we summarize the latest progresses in the field with a major focus on preclinical studies in validation of neddylation modification as a promising anticancer target.

Keywords: Apoptosis; Autophagy; Cancer target; Cell cycle arrest; Cullin RING ligase; MLN4924; Neddylation; Senescence.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Figure 1
Figure 1. The process of protein modification by neddylation
Neddylation is a process that conjugates NEDD8, an ubiquitin-like molecule, to targeted protein substrates via enzymatic cascades involving NEDD8-activating enzyme E1, NEDD8-conjuagating enzyme E2 and substrate-specific NEDD8-E3 ligases. Shown are reported neddylation E3s and substrates. The substrates were divided into cullins and non-cullins. N8: NEDD8.
Figure 2
Figure 2. Neddylation activates CRLs to regulate tumorigenesis
In normal cells, neddylation and deneddylation are kept in a balanced status to ensure hemostasis. During tumorigenesis, CRLs are activated to selectively promote ubiquitylation and degradation of tumor suppressors, thus accelerating tumor growth. Blockage of neddylation by MLN4924 or other E2s/E3s inhibitors would inactivate CRLs to cause the accumulation of tumor suppressor substrates to inhibit tumor growth.
Figure 3
Figure 3. MLN4924 triggers multiple anticancer mechanisms
1) MLN4924, acting alone, inactivates CRLs by inhibiting cullin neddylation to cause the accumulation of multiple tumor-suppressive substrates, leading to blockage of tumor angiogenesis and inflammatory responses, induction of senescence or apoptosis in cancer cells, and protective autophagy which serves as an overall survival signal to cancer cells. 2) MLN4924, in combination with chemoradiation, sensitizes resistant cancer cells to conventional therapies.
Figure 4
Figure 4. Rational drug combinational design
Neddylation inactivation by MLN4924 triggers protective autophagy in cancer cells through the blockage of mTOR signals via the accumulation of DEPTOR and the activation of the HIF1α-DDIT4/REDD1-TSC1/2 axis. Thus, combination of MLN4924 with small molecule inhibitors of autophagy (e.g. chloroquine) leads to an increased suppression of tumor growth by enhancing NOXA-dependent apoptosis via triggering DNA damage and ROS generation.
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