RETRACTED ARTICLE: Targeting KDM4A-AS1 represses AR/AR-Vs deubiquitination and enhances enzalutamide response in CRPC

Zhang, Boya; Zhang, Mingpeng; Yang, Yanjie; Li, Qi; Yu, Jianpeng; Zhu, Shimiao; Niu, Yuanjie; Shang, Zhiqun

doi:10.1038/s41388-021-02103-x

Cited by 25 publications

(23 citation statements)

References 48 publications

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“…KDM4A-AS1 expression was elevated in castrationresistant prostate cancer. Importantly, ASOs targeting KDM4A-AS1 significantly reduced the growth of tumors with enzalutamide resistance (Zhang et al, 2022).…”

Section: Protein Stabilitymentioning

confidence: 99%

Natural antisense transcripts as drug targets

Khorkova

Stahl

Joji

et al. 2022

Front. Mol. Biosci.

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The recent discovery of vast non-coding RNA-based regulatory networks that can be easily modulated by nucleic acid-based drugs has opened numerous new therapeutic possibilities. Long non-coding RNA, and natural antisense transcripts (NATs) in particular, play a significant role in networks that involve a wide variety of disease-relevant biological mechanisms such as transcription, splicing, translation, mRNA degradation and others. Currently, significant efforts are dedicated to harnessing these newly emerging NAT-mediated biological mechanisms for therapeutic purposes. This review will highlight the recent clinical and pre-clinical developments in this field and survey the advances in nucleic acid-based drug technologies that make these developments possible.

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Section: Protein Stabilitymentioning

confidence: 99%

Natural antisense transcripts as drug targets

Khorkova

Stahl

Joji

et al. 2022

Front. Mol. Biosci.

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“…The altered lncRNA expression has been tied to abnormal tumor cell apoptotic, migratory, invasive, and proliferative activity, with several lncRNAs having been identified as key regulators of the acquisition of castration resistance in PCA [ 196 , 197 ]. KDM4A-AS1, for example, is a lncRNA that is upregulated in the CRPC cells, wherein it can promote AR/AR-V deubiquitination, thus protecting them against downregulation [ 198 ]. As such, KDM4A-AS1 can promote significantly enhanced tumor cell viability, migration, and proliferation in vitro as well as more robust tumor growth in vivo [ 198 ].…”

Section: Non-ar Pathwaysmentioning

confidence: 99%

“…KDM4A-AS1, for example, is a lncRNA that is upregulated in the CRPC cells, wherein it can promote AR/AR-V deubiquitination, thus protecting them against downregulation [ 198 ]. As such, KDM4A-AS1 can promote significantly enhanced tumor cell viability, migration, and proliferation in vitro as well as more robust tumor growth in vivo [ 198 ]. PCBP1-AS1 has also been shown to prevent ubiquitin-proteasome pathway-mediated AR/AR-V7 degradation through the binding to the NTD of these receptor proteins [ 199 , 200 ].…”

Section: Non-ar Pathwaysmentioning

confidence: 99%

Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

Mao

Yang

Li³

et al. 2022

Cancers

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Despite aggressive treatment and androgen-deprivation therapy, most prostate cancer patients ultimately develop castration-resistant prostate cancer (CRPC), which is associated with high mortality rates. However, the mechanisms governing the development of CRPC are poorly understood, and androgen receptor (AR) signaling has been shown to be important in CRPC through AR gene mutations, gene overexpression, co-regulatory factors, AR shear variants, and androgen resynthesis. A growing number of non-AR pathways have also been shown to influence the CRPC progression, including the Wnt and Hh pathways. Moreover, non-coding RNAs have been identified as important regulators of the CRPC pathogenesis. The present review provides an overview of the relevant literature pertaining to the mechanisms governing the molecular acquisition of castration resistance in prostate cancer, providing a foundation for future, targeted therapeutic efforts.

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“…Notably, this study found that 20% of AR transcripts had a 3 kb deletion within the normally 6.7 kb long 3′ UTR and that this shorter AR UTR splice variant, which was also detectable in patients’ post-treatment tumor samples and PC patient sera, had a significantly increased stability/half-life, which potentially conferred a survival advantage to the tumor cells. Yet another recent study found that an oncogenic lncRNA KDM4A-AS1, which notably increased in CRPC cell lines and cancer tissues and was associated with unfavorable outcomes, promoted the stability of the USP14-AR-FL/AR-Vs complex and the de-ubiquitination of AR/AR-Vs. By repressing proteolysis of AR-FL/AR-Vs, the lncRNA KDM4A-AS1 enhanced CRPC drug resistance to enzalutamide [ 112 ]. Importantly, KDM4A-AS1 is a hypoxia-responsive gene and is known to be transactivated by HIF-1α.…”

Section: How Hypoxia May Be Culpable In Resistance To Androgen/ar-tar...mentioning

confidence: 99%

Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer

Jinna

Rida²,

Smart³

et al. 2022

IJMS

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Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes.

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RETRACTED ARTICLE: Targeting KDM4A-AS1 represses AR/AR-Vs deubiquitination and enhances enzalutamide response in CRPC

Cited by 25 publications

References 48 publications

Natural antisense transcripts as drug targets

Natural antisense transcripts as drug targets

Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer

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