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CDK13 Upregulation-Induced Formation of the Positive Feedback Loop Among Circcdk13, Mir-212-5P/Mir-449A and E2F5 Contributes To

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CDK13 Upregulation-Induced Formation of the Positive Feedback Loop Among Circcdk13, Mir-212-5P/Mir-449A and E2F5 Contributes To Qi et al. Journal of Experimental & Clinical Cancer Research (2021) 40:2 https://doi.org/10.1186/s13046-020-01814-5 RESEARCH Open Access CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis Jin-Chun Qi1†, Zhan Yang1†, Tao Lin1†, Long Ma1, Ya-Xuan Wang1, Yong Zhang1, Chun-Cheng Gao1, Kai-Long Liu1, Wei Li1, An-Ning Zhao1, Bei Shi1, Hong Zhang1, Dan-Dan Wang1, Xiao-Lu Wang1, Jin-Kun Wen2 and Chang-Bao Qu1* Abstract Background: Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa. Methods: The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real- time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo. Results: Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation. (Continued on next page) * Correspondence: [email protected] †Jin-Chun Qi, Zhan Yang and Tao Lin contributed equally to this work. 1Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang 050000, China Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Qi et al. Journal of Experimental & Clinical Cancer Research (2021) 40:2 Page 2 of 18 (Continued from previous page) Conclusions: These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance. Keywords: Prostate cancer, CDK13, circRNAs biogenesis, E2F5, Drug resistance Background castration-resistant prostate cancer (mCRPC) samples, Prostate cancer (PCa) is one of the most common malig- and CDK12 loss results in highly recurrent gains at loci of nancies and the second leading cause of cancer-related genes involved in the cell cycle and DNA replication [18– death in men [1, 2]. Although organ-confined PCa can 20]. However, much less is known regarding CDK13 ex- be effectively treated by radical prostatectomy or radi- pression and function in PCa. ation therapies, androgen deprivation therapy (ADT) is Circular RNAs (circRNAs) are a novel class of non- first-line treatment for metastatic PCa. Once hormonal coding RNA characterized by the presence of a covalent resistance occurs, PCa progresses rapidly, and advanced bond linking the 3′ and 5′ ends generated by back- PCa is usually fatal within 18 months [3, 4]. Currently, splicing [21]. Emerging evidences have shown that cir- several compounds, including abiraterone acetate [5], cRNAs are frequently deregulated in various diseases and enzalutamide [6], sipuleucel-T [7], alpharadin [8], and have distinct and specific functions in a number of bio- docetaxel [9] have been used to help treat PCa. Unfortu- logical processes, such as proliferation, apoptosis or drug nately, adverse side effects of the treatment and drug re- resistance [22, 23]. Our previous study revealed that the sistance often lead to treatment failure [10]. Therefore, RNA-binding protein RBM25 induces circAMOTL1L bio- there is an urgent need to further understand the mo- genesis by directly interacting with circAMOTL1L, p53 lecular mechanism involved in prostate carcinogenesis upregulates circAMOTL1L expression through activating and drug resistance. the RBM25 gene, whereas p53 downregulation in PCa Although the molecular mechanisms driving prostate cells facilitates epithelial-mesenchymal transition (EMT) carcinogenesis are complex, the dysregulation of cell pro- [24]. Recently, we found that circACTA2 is able to medi- liferation is a fundamental feature of all types of cancer. ate NRG-1-ICD regulation of its parental gene ACTA2 Cell proliferation is coupled with cell cycle progression, (alpha-actin gene) in vascular smooth muscle cells via and mammalian CDKs are essential for driving each cell NRG-1-ICD/circACTA2/miR-548f-5p axis [25]. Remark- cycle phase. Accumulating evidence has suggested that ably, several lines of evidence suggest that some circRNAs tumor-associated cell cycle disorders are often mediated play important roles in the resistance of cancer cells to an- by alterations in cyclin-dependent kinase (CDK) activity. ticancer drugs. For example, circAKT3 upregulates Mis-regulated CDKs induce unscheduled proliferation PIK3R1 to enhance cisplatin resistance in gastric cancer [11]. It has been well known that mammalian cells contain via inhibition of miR-198 [22]. circ_0025202 suppresses at least 13 CDKs [11]. Of these, CDK1-CDK6, CDK10 and tumor growth and enhances tamoxifen sensitization via CDK11 are all involved in cell cycle control [11–13]. regulating the miR-182-5p/FOXO3a axis in breast cancer CDK7,CDK8 and CDK9 have activities that are different [26]. Circular RNA cESRP1 increases small cell lung can- from cell cycle control, these 3 CDKs can phosphorylate cer responsiveness to chemotherapy by sequestering miR- the carboxyl-terminal domain (CTD) of RNA polymerase 93-5p to inhibit the TGF-β pathway [27]. So far, the mul- II and exert actions in transcriptional regulation [12–14]. tiple mechanisms that have been reported to be associated CDK12 and CDK13 bind to L-type cyclins (CycL) and with the development of drug resistance involve alter- regulate alternative RNA splicing [15, 16]. A recent study ations in drug targets, drug metabolism, cancer stem cell shows that knocking out CDK13 leads to abnormal ex- population, DNA damage repair, as well as cell survival pression of several genes involved in a variety of biological and death signals [28]. Despite the important roles of cir- processes including cell growth regulation [17]. Notably, cRNAs in prostate carcinogenesis and drug resistance, lit- both CDK12 and CDK13 knockdown affect the expression tle is known about the role of circRNAs derived from the of genes involved in RNA processing, but CDK13- same parental gene, which can regulate the transcription regulated gene sets are not affected by CDK12 knock- of the parental gene by binding to RNA polymerase II down. These evidences clearly suggest that human CDK [29], and thus form the positive feedback loop between functions do not overlap with each other, probably reflect- circRNAs and their parental genes to induce prostate car- ing tissue-specific and fine-tuned regulation of cell cycle cinogenesis and drug resistance. regulation. Importantly, several recent studies reported In this study, we report that CDK13 is significantly up- that CDK12 expression is dysregulated in metastatic regulated in PCa, and transcriptional activation of Qi et al. Journal of Experimental & Clinical Cancer Research (2021) 40:2 Page 3 of 18 endogenous CDK13 promotes E2F5 expression by facili- the manufacturer’s protocols. The miR-449a and miR- tating the formation of circCDK13, which in turn 212-5p mimics, mimic NC, inhibitors, inhibitor NC, cir- sponges miR-212-5p/449a and thus relieves their repres- cRNA probe and its controls were purchased from Gen- sion of the E2F5 expression,
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