Targeting JWA for Cancer Therapy: Functions, Mechanisms and Drug Discovery

Ding, Kan; Liu, Xia; Wang, Luman; Zou, Lu; Jiang, Xuqian; Li, Aiping; Zhou, Jianwei

doi:10.3390/cancers14194655

Cited by 5 publications

(4 citation statements)

References 139 publications

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“…JAC1 specifically binds to YY1, thereby relieving YY1-mediated ARL6IP5 transcriptional repression and increasing the expression of ARL6IP5 [ 184 ]. ARL6IP5 acts as a tumor suppressor gene in tumor cells and is associated with multiple functions, including angiogenesis, proliferation, apoptosis, metastasis, and resistance to chemotherapy [ 186 , 187 , 188 ]. Its downregulation in tumors is correlated with poor prognosis [ 184 ].…”

Section: The Roles Of Yy1 In Tumor Development and Progressionmentioning

confidence: 99%

“…Enhanced sensitivity to radiotherapy in HT29 and SCCVII cell lines [171] Enhanced sensitivity to radiotherapy in mouse model [171] RRx-001 already passed phase I clinical trial. RRx-001 was well tolerated, with no notable toxicities nor adverse effects (NCT01359982) RRx-001 is currently in a phase 2 clinical trial [171][172][173] Inhibited Ikβ kinase complex [172,173] Inhibited Iκβ kinase complex [172,173] Betulinic acid Downregulated YY1 in MDA-MB-453 cell line [75] Downregulated YY1 in BT474 xenografted nude mice [75] Downregulated YY1-dependent HER2 expression in the MDA-MB-453 cell line [75] Decreased tumor growth [75] Induced cell cycle arrest in G 2 /M phase [181] Decreased β2-microglobulin mRNA [181] Decreased cell proliferation [180,181] Inhibited tumor growth and metastases [181,182] JAC1 Upregulated expression of ARL6IP5 [186,188] Inhibited formation of neo-vessels in gastric-cancer-bearing nude mice [188] Downregulated HER2 expression [186] Inhibited angiogenesis of melanoma [188] Reduced cell migration [186] YY1BM (LINC00278) Downregulated eEF2K; induced apoptosis of ESCC cells [194] Increased apoptosis [194] Synthetic peptides (YPB and OPB) Disrupted YY1-EZH2 [197] Inhibited tumor growth in xenograft of MDA-MB-231 cells [197] Reduced H3K27me3 [197] Upregulated PTENP1 and PTEN expression [197] Inhibited cell proliferation of TNBC cell lines (MDA-MB-231 and MDA-MB-453) [197] Reduced viability, reduced cell migration, in MDA-MB-231 [197] Table 3. Cont.…”

Section: Deta-nonoatementioning

confidence: 99%

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Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions

Hosea,

Hillary,

et al. 2023

Cancers

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Cancer represents a significant and persistent global health burden, with its impact underscored by its prevalence and devastating consequences. Whereas numerous oncogenes could contribute to cancer development, a group of transcription factors (TFs) are overactive in the majority of tumors. Targeting these TFs may also combat the downstream oncogenes activated by the TFs, making them attractive potential targets for effective antitumor therapeutic strategy. One such TF is yin yang 1 (YY1), which plays crucial roles in the development and progression of various tumors. In preclinical studies, YY1 inhibition has shown efficacy in inhibiting tumor growth, promoting apoptosis, and sensitizing tumor cells to chemotherapy. Recent studies have also revealed the potential of combining YY1 inhibition with immunotherapy for enhanced antitumor effects. However, clinical translation of YY1-targeted therapy still faces challenges in drug specificity and delivery. This review provides an overview of YY1 biology, its role in tumor development and progression, as well as the strategies explored for YY1-targeted therapy, with a focus on their clinical implications, including those using small molecule inhibitors, RNA interference, and gene editing techniques. Finally, we discuss the challenges and current limitations of targeting YY1 and the need for further research in this area.

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Section: The Roles Of Yy1 In Tumor Development and Progressionmentioning

confidence: 99%

Section: Deta-nonoatementioning

confidence: 99%

Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions

Hosea,

Hillary,

et al. 2023

Cancers

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“…Therefore, JWA is considered a tumor suppressor. In addition, JWA targeting has been proposed as a potential therapeutic strategy not only for GC but also for several other cancers [55]. In cancers, JWA is downregulated by degradation following its ubiquitination on lysine residues mediated by interaction with RNF185.…”

Section: Rnf185mentioning

confidence: 99%

Role of the Mitochondrial E3 Ubiquitin Ligases as Possible Therapeutic Targets in Cancer Therapy

Di Gregorio,

Appignani,

Flati

2023

IJMS

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Ubiquitination is a post-translational modification that targets specific proteins on their lysine residues. Depending on the type of ubiquitination, this modification ultimately regulates the stability or degradation of the targeted proteins. Ubiquitination is mediated by three different classes of enzymes: the E1 ubiquitin-activating enzymes, the E2 ubiquitin-conjugating enzymes and, most importantly, the E3 ubiquitin ligases. E3 ligases are responsible for the final step of the ubiquitin cascade, interacting directly with the target proteins. E3 ligases can also be involved in DNA repair, cell cycle regulation and response to stress; alteration in their levels can be involved in oncogenic transformation and cancer progression. Of all the six hundred E3 ligases of the human genome, only three of them are specific to the mitochondrion: MARCH5, RNF185 and MUL1. Their alterations (that reflect on the alteration of the mitochondria functions) can be related to cancer progression, as underlined by the increasing research performed in recent years on these three mitochondrial enzymes. This review will focus on the function and mechanisms of the mitochondrial E3 ubiquitin ligases, as well as their important targets, in cancer development and progression, also highlighting their potential use for cancer therapy.

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“…JWA gene, also known as arl6ip5, is originally cloned from retinoic acid (RA) -induced differentiation model in human bronchial epithelial (HBE) cells. JWA is an environmental response and tumor suppressor gene [14,15]. The low expression of JWA gene is associated with the poor prognosis of gastric cancer patients; and high expression of JWA inhibits the proliferation, invasion and migration of breast cancer, pancreatic cancer, esophageal squamous cell carcinoma, NSCLC and other cancers [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

JAC4 Enhances Radiotherapy Effect of NSCLC and Reduces Normal Lung Injury Through Differential Regulation of JWA-mediated DNA Repair

Wang¹,

Ni²,

Ding³

et al. 2023

Preprint

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More than 50% of patients with non-small cell lung cancer (NSCLC) are treated with radiotherapy (RT) during different phases of treatment. However, radiation pneu-monitis (RP) and resistance often lead to RT failure in NSCLC patients. JWA, a tumor suppressor gene, is known to enhance DNA damage in gastric cancer cells while protect normal cells from DNA damage induced by cisplatin. Recently, we have re-ported that JWA agonist compound 4 (JAC4) effectively protects intestinal epithelium from RT triggered damage in mice. However, the potential synergistic and attenuated effects of JAC4 in chest RT of lung cancer are not been illuminated. The aim of this study was to investigate the effects of JAC4 on the radiotoxicities of both NSCLC and normal lung tissue. CCK-8 and colony formation assays showed that JAC4 played a bidirectional role in radiation-treated SPCA-1 and BEAS-2B cells. Western blotting and immunofluorescence assays showed that JAC4 in combination with RT increased DNA damage and apoptosis in SPCA-1 cells, while the opposite effect was observed in BEAS-2B cells. Mechanistically, JAC4 inhibited homologous recombination repair (HR) and non-homologous end joining (NHEJ) in SPCA-1 cells, but not in normal cells. JAC4 increased antioxidant capacity, and reduced oxidative stress and inhibited nu-clear factor Kappa-B (NF-κB, P65) translocation to the nucleus in BEAS-2B cells. Im-portantly, the bidirectional roles of JAC4 on RT were reversed by siJWA in both SPCA-1 and BEAS-2B cells. Finally, the bidirectional effects of JAC4 in combination with RT were further validated in NSCLC xenograft model mice. In conclusion, JAC4 enhanced effect of RT on tumor growth while alleviated RP and lung injury. Our re-sults may provide new strategy for optimizing RT regimen for NSCLC.

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Targeting JWA for Cancer Therapy: Functions, Mechanisms and Drug Discovery

Cited by 5 publications

References 139 publications

Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions

Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions

Role of the Mitochondrial E3 Ubiquitin Ligases as Possible Therapeutic Targets in Cancer Therapy

JAC4 Enhances Radiotherapy Effect of NSCLC and Reduces Normal Lung Injury Through Differential Regulation of JWA-mediated DNA Repair

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