DDIAS, DNA damage-induced apoptosis suppressor, is a potential therapeutic target in cancer

Abstract

Increasing evidence indicates that DNA damage-induced apoptosis suppressor (DDIAS) is an oncogenic protein that is highly expressed in a variety of cancers, including colorectal cancer, lung cancer, breast cancer, and hepatocellular carcinoma (HCC). The discovery of DDIAS as a novel therapeutic target and its role in human cancer biology is fascinating and noteworthy. Recent studies have shown that DDIAS is involved in tumorigenesis, metastasis, DNA repair and synthesis, and drug resistance and that it plays multiple roles with distinct binding partners in several human cancers. This review focuses on the function of DDIAS and its regulatory proteins in human cancer as potential targets for cancer therapy, as well as the development and future prospects of DDIAS inhibitors.

Introduction

DNA damage-induced apoptosis suppressor (DDIAS) was first discovered as a human homolog (hNoxin) of mouse noxin via genomic analysis of colorectal cancer patients and large-scale siRNA screening aimed at searching for cancer-related genes^1,2. DDIAS was named based on its antiapoptotic properties in response to DNA repair in cancer cells.

DDIAS is highly expressed in several human cancers, including colorectal cancer, lung cancer, breast cancer and hepatocellular carcinoma (HCC), and stimulates cancer cell proliferation and cell cycle progression^2,3,4,5. DDIAS plays a vital role in tumorigenesis, metastasis, DNA repair and drug resistance by inhibiting cell death mediated by DNA damage agents, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and gefitinib in lung cancer^2,5,6,7,8. In HCC, DNA copy number amplification of DDIAS has been observed³. Interestingly, DDIAS interacts with various binding partners to drive numerous processes in the membrane, cytoplasm and nucleus through various extracellular signals.

Although DDIAS studies on the novel cancer-related processes are still lacking, DDIAS appears to play a key role in carcinogenesis, particularly in lung, liver and colorectal cancers. DDIAS is not a well-known gene to most cancer researchers even though it is noteworthy as a novel cancer therapeutic target. In this review, we discuss various aspects of DDIAS, including transcriptional regulation, degradation, DNA repair, and resistance to apoptosis, and suggest prospective cancer treatments by inhibiting DDIAS-related cellular functions.

Molecular features of DDIAS

The DDIAS gene (noxin, C11orf82, GeneID220042) encodes 998 amino acids and consists of six exons with a translation initiation site at the third exon. DDIAS features a DNA-binding domain C (DBD C) in the N-terminal region (amino acids 8–123), which is also found in replication protein A (RPA), a nuclear single-stranded DNA-binding protein. DBD C is essential for forming heterotrimeric complexes with RPA1 with RPA2 and RPA3 for replication, recombination and repair, and interactions with nuclear proteins^9,10,11. The DDIAS gene is located on human chromosome 11 and is conserved (70% similarity at the DNA level) in the rat and mouse genomes (rat chromosome 1 and mouse chromosome 7). Although DDIAS has been recognized as a human homolog of mouse nitric oxide-inducible (noxin), a sequence comparison of the DDIAS protein with mouse noxin reveals high homology only in the N-terminal region containing the DBD C (80.5%; amino acids 1–123) and lower homology throughout the remainder of the protein sequences (33.2%; amino acids 124–998), despite conserved several sequences (Fig. 1). The DDIAS protein sequence is enriched with serine (132 serine residues), indicating that phosphorylation of these residues might be a potential modification. Similar to mouse noxin, DDIAS carries putative sites of phosphorylation by DNA-PK, ATM, cdc2, CDK5, CKII, p38 mitogen activated protein kinase (p38MAPK), RSK, PKA, and PKC (NetPhos 3.1). Recently, Akimov and colleagues reported that DDIAS is ubiquitinated at lysine386, lysine500 and lysine807, as previously discovered using the UbiSite method¹² (Fig. 1).

Fig. 1: Schematic representation of the DDIAS protein.

a, b Comparison of rat, mouse, and human DDIAS proteins. Sequence comparison of human DDIAS protein with mouse DDIAS (noxin) revealed high homology in the N-terminal region containing the DBD C (80.5%; amino acids 1–123) and less homology throughout the rest of the proteins (33.2%; amino acids 124–998). Nuc, nuclear localization signals (red); Zn, zinc-finger-like domain (pink); DNA-PK, DNA-PK phosphorylation consensus sequences (yellow); Akt or ATM, Akt or ATM phosphorylation consensus sequences (yellow); DBD C, DNA binding domain C (Pink); MED29, mediator complex subunit 29 (blue). Potential ubiquitination sites in DDIAS (K386, K500, and K807) are shown.

Regulation of DDIAS expression

DDIAS expression patterns

In normal human tissues, low expression of DDIAS has been detected in the lung, stomach, thymus, colon and heart, while high expression has been detected in the human testis, pancreas and prostate². However, DDIAS mRNA levels are significantly higher in lung, breast, and colorectal cancer tissues and cancer cell lines than in normal tissues or cells^2,3. HCC is characterized by DDIAS overexpression with DNA copy number amplification on chromosome 11q14.1⁵. DDIAS expression is induced by ultraviolet (UV) irradiation, and its level is highest in the S phase of the cell cycle in cancer and normal cells. Similar to DDIAS, mouse noxin is highly expressed in the testis^1,2. Similarly, numerous stressors, such as gamma ray irradiation, UV irradiation, NO donors, hydrogen peroxide, adriamycin, and cytokines, stimulate the production of mouse noxin. However, mouse noxin expression is highest in cells in the G2/M phase or after exposure to nocodazole, a G2/M arrest inducer.

The Human Protein Atlas revealed that DDIAS is found mainly in the cytoplasm. Endogenous DDIAS is present in the cytoplasm of lung cancer cells and tissues, as well as the nucleus of HCC cells^4,5,13. In NIH3T3 cells, endogenous mouse noxin is found in the cytoplasm and the nucleus; however, it accumulates in the nucleus in response to exposure to the nitric oxide donor SNAP¹.

Transcriptional regulation of DDIAS

DDIAS is a target gene of nuclear factor of activated T cells 1 (NFATc1, NFAT2) in lung cancer⁶. In a DDIAS promoter analysis, potential binding sites for various transcription factors, such as p300, SP1, C/EBP, or NFAT, were identified. Among these transcription factors, dephosphorylated NFATc1 activates the transcription of DDIAS by binding to NFAT consensus sequences in the DDIAS promoter. DDIAS gene expression is stimulated by phorbol 12-myristate 13-acetate and the calcium ionophore A23187 and suppressed by the calcineurin inhibitor cyclosporin A, which activate and inhibit NFATc1, respectively (Fig. 2a). Additionally, tissue array immunostaining revealed a correlation between DDIAS and NFATc1 expression in human lung cancers⁶. Despite the importance of the NFAT family in the immune response, recent studies have indicated that activation or overexpression of NFATc1 in human solid tumors and hematological malignancies is associated with tumor progression^14,15.

Fig. 2: Regulation of DDIAS expression.

a Activated NFAT2 regulates DDIAS transcription. b In response to EGF, MEK5/ERK5/MEF2B pathways induce DDIAS expression. c DDIAS ubiquitination mediated by HSP70/CHIP regulates DDIAS protein turnover.

Although DDIAS expression is induced by UV irradiation of normal and cancer cells², the mechanism underlying DDIAS-mediated transcriptional regulation by UV irradiation is not fully understood. UV irradiation generally stimulates mitogen-activated protein kinase (MAPK) and ATM pathways and the activation of transcription factors such as p53, NF-kB, AP-1, NFAT, and Nrf2^16,17. Similarly, the induction of mouse noxin function mediated by stress stimuli, including UV irradiation, depends on p53¹.

In addition to UV exposure, DDIAS expression is induced by serum or epidermal growth factor (EGF)^2,13. Previous studies have demonstrated that extracellular signal-regulated kinase 5 (ERK5) phosphorylates myocyte enhancer factor-2 (MEF2) family proteins and serum glucocorticoid-inducible kinase, all of which are essential for entry into the S phase of the cell cycle^18,19. DDIAS expression is induced by ERK5 and MEF2 in response to EGF^13,20. Genetic or pharmacological inhibition of ERK5 suppresses DDIAS expression by EGF exposure. The overexpression of constitutively active MEK5 enhances DDIAS expression (Fig. 2b). In chromatin immunoprecipitation (ChIP) assays, MEF2B (a downstream target of ERK5) exhibited sequence-specific binding to the MEF2-binding site in the DDIAS promoter after EGF treatment. Moreover, overexpression of MEF2B increased the EGF-mediated induction of DDIAS expression, whereas knockdown of MEF2B attenuated this effect.

Posttranslational regulation of DDIAS

DDIAS stability is regulated by E3 U-box-dependent ubiquitin ligase carboxyl terminus of HSP70-interacting protein (CHIP)-mediated proteasomal degradation²¹. We first identified CHIP as an interacting partner of DDIAS by yeast two-hybrid screening. E3 ubiquitin ligase CHIP physically associates with both the N- and C-terminal regions of DDIAS, allowing this protein to be targeted for proteasomal degradation and thereby reducing the DDIAS half-life in the cytoplasm (Fig. 2c). CHIP deletion study demonstrated a tetratricopeptide repeat (TPR) domain and the U-box are essential for DDIAS ubiquitination. HSP70-bound DDIAS is recruited to the CHIP E3 ligase via the TPR domain, suggesting that DDIAS is a client protein of HSP70. Since CHIP is a chaperone-associated U box-containing E3 ligase, it depends on Hsp70/Hsp90 chaperones. These chaperones interact with oncogenic clients such as c-Myc, hypoxia inducible factor 1a (HIF-1a), NF-kB/p65, and DDIAS^21,22,23,24, implying that CHIP is a tumor suppressor.

Molecular mechanisms of DDIAS in Cancers

DDIAS executes a variety of cellular tasks with its different binding partners (Table 1). High expression of DDIAS in cancer contributes to malignancies mediated via a variety of mechanisms (Fig. 3). The functions of DDIAS associated with cancer are discussed herein.

Table 1 Proteins interacting with DDIAS.

Fig. 3: Oncogenic functions of DDIAS mediated via multiple pathways.

a DDIAS promotes DNA synthesis and DSB (double-strand break) repair in human cancers. b DDIAS enhances the proliferation and metastasis of cancer cells mediated by STAT3 phosphorylation by competing with PTPRM. c DDIAS prevents cancer cells from undergoing apoptosis by inhibiting the p38 MAPK/p53/p21 pathway and TRAIL-mediated DISC formation. d DDIAS contributes to TRAIL and tamoxifen resistance.

DNA synthesis and repair

DDIAS overexpression accelerates the G1-S phase transition by enhancing DNA synthesis in HCC⁵. DDIAS interacts with DNA polymerase α, suggesting that DDIAS may boost de novo DNA synthesis by promoting the formation of DNA polymerase-primase complexes (Fig. 3a). DDIAS overexpression promotes cellular proliferation, colony formation, cellular migration and in vivo tumorigenicity, whereas DDIAS knockdown attenuates these effects.

On the basis of computational approaches such as evolutionary rate covariation, a recent study revealed 17,487 mammalian genes coevolved in six distinct DNA repair pathways. Among these coevolved proteins, DDIAS was identified as a novel factor in double-strand break (DSB) repair based on its coevolution with homologous recombination (HR)²⁵. It is involved in a DSB repair mechanism mediating nonhomologous end-joining^26,27. DDIAS depletion resulted in DSB accumulation, as indicated by ATM kinase activation and 53BP1 foci induction, and defective HR (Fig. 3a). Similarly, a previous report showed an increase in H2AXγ, a marker of DNA DSBs, and comet formation, a measure of DNA strand breaks, with cells depleted of DDIAS². Furthermore, DDIAS carries an oligonucleotide/oligosaccharide-binding-fold domain similar to the single-strand DNA-binding domain of RPA². This domain is required for replication, recombination and repair processes such as HR²⁸, providing evidence supporting the involvement of DDIAS in DNA repair.

Proliferation and metastasis of cancer cells

The activation of signal transducer and activator of transcription 3 (STAT3) plays a critical role in cancer cell proliferation, survival, metastasis, and self-renewal^29,30,31,32. Phosphorylated STAT3 enters the nucleus and induces the transcription of target genes, including survivin, Bcl-2, Mcl-1, c-Myc, cyclin D1, slug, and matrix metalloproteinase-2^33,

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Acknowledgements

This work was supported by the National Research Foundation (NRF-2017R1A2B2011936) and the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM5192221).

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Authors and Affiliations

1. Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Republic of Korea

   Joo-Young Im, Mi-Jung Kang, Bo-Kyung Kim & Misun Won

2. University of Science and Technology (UST), Daejeon, 34113, Republic of Korea

   Bo-Kyung Kim & Misun Won

3. R&D Center, OneCureGEN Co., Ltd., Daejeon, 34141, Republic of Korea

   Bo-Kyung Kim & Misun Won

Contributions

J.Y.I., M.J.K., and B.K.K. collected the literature and conceived the review. J.Y.I. wrote the manuscript. J.Y.I. and M.W. revised and edited the manuscript.

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Correspondence to Joo-Young Im or Misun Won.

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Im, JY., Kang, MJ., Kim, BK. et al. DDIAS, DNA damage-induced apoptosis suppressor, is a potential therapeutic target in cancer. Exp Mol Med 55, 879–885 (2023). https://doi.org/10.1038/s12276-023-00974-6

• Received: 03 November 2022

• Revised: 11 January 2023

• Accepted: 19 January 2023

• Published: 01 May 2023

• Issue Date: May 2023

• DOI: https://doi.org/10.1038/s12276-023-00974-6

• Springer Nature Limited