Overexpression of CAPN2 promotes cell metastasis and proliferation via AKT/mTOR signaling in renal cell carcinoma

Miao, Chenkui; Liang, Chao; Tian, Ye; Xu, Aiming; Zhu, Jingjing; Zhao, Kai; Zhang, Jianzhong; Hua, Yingqi; Liu, Shouyong; Dong, Huiyu; Zhang, Chao; Su, Shifeng; Li, Pu; Qin, Chao; Wang, Zengjun

doi:10.18632/oncotarget.22083

Cited by 21 publications

(18 citation statements)

References 37 publications

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“…In MeCP2 ChIP-Seq in MDA-MB-468 cells, we found that MeCP2 binds to multiple novel targets not previously associated with MeCP2 function in the context of breast cancer. Some of these included the following genes: a) SSU72 Homolog, RNA Polymerase II CTD Phosphatase (SSU72), a protein phosphatase that catalyzes the dephosphorylation of the C-terminal domain of RNA polymerase II ( 66 ); b) CAPN2 (Calpain 2), a calcium-sensitive cysteine protease ( 67 ); c) Plexin B2 (PLXNB2), a class B transmembrane receptor that participates in axon guidance and cell migration in response to semaphorins ( 68 ); d) Zinc Finger SWIM-Type Containing 4 (ZSWIM4); e) RUNX Family Transcription Factor 3 (RUNX3) a transcription factor that functions as a tumor suppressor and is frequently deleted or transcriptionally silenced in cancer ( 69 , 70 ), and f) Solute Carrier Family 45 Member 4 (SLC45A4) ( Figure 1B ). Additionally, in MCF7 some of the notable genes included a) Ubiquitin Specific Peptidase 34 (USP34), a ubiquitin hydrolase that removes conjugated ubiquitin from AXIN1 and AXIN2, acting as a regulator of Wnt signaling pathway ( 71 ); b) Maltase–Glucoamylase (MGAM), an enzyme that plays a role in the digestion of starch ( 72 ); c) GDP-Mannose 4,6-Dehydratase (GMDS), an enzyme that participates in the synthesis of GDP-fucose from GDP-mannose ( 73 ); d) Solute Carrier Family 45 Member 4 (SLC45A4); e) CCDC26 Long Non-Coding RNA (CCDC26), a lncRNA class associated with Malignant Glioma and Astrocytoma ( 74 , 75 ); and f) Sidekick Cell Adhesion Molecule 1 (SDK1) ( Figure 1C ).…”

Section: Resultsmentioning

confidence: 99%

“…We also found that MeCP2 binds to genomic regions devoid of CpG methylation such as for USP34, MGAM, GMDS, SLC45A4, SSU72, CAPN2 and PLXN2 ( Figures S1B–C ). Similarly, while these are novel targets of MeCP2, many have been implicated in diverse cancers ( 67 , 71 , 88 – 92 ). This further shows the complexity of MeCP2 binding across the genome.…”

Section: Resultsmentioning

confidence: 99%

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Identification of Novel MeCP2 Cancer-Associated Target Genes and Post-Translational Modifications

et al. 2020

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Abnormal regulation of DNA methylation and its readers has been associated with a wide range of cellular dysfunction. Disruption of the normal function of DNA methylation readers contributes to cancer progression, neurodevelopmental disorders, autoimmune disease and other pathologies. One reader of DNA methylation known to be especially important is MeCP2. It acts a bridge and connects DNA methylation with histone modifications and regulates many gene targets contributing to various diseases; however, much remains unknown about how it contributes to cancer malignancy. We and others previously described novel MeCP2 post-translational regulation. We set out to test the hypothesis that MeCP2 would regulate novel genes linked with tumorigenesis and that MeCP2 is subject to additional post-translational regulation not previously identified. Herein we report novel genes bound and regulated by MeCP2 through MeCP2 ChIP-seq and RNA-seq analyses in two breast cancer cell lines representing different breast cancer subtypes. Through genomics analyses, we localize MeCP2 to novel gene targets and further define the full range of gene targets within breast cancer cell lines. We also further examine the scope of clinical and pre-clinical lysine deacetylase inhibitors (KDACi) that regulate MeCP2 post-translationally. Through proteomics analyses, we identify many additional novel acetylation sites, nine of which are mutated in Rett Syndrome. Our study provides important new insight into downstream targets of MeCP2 and provide the first comprehensive map of novel sites of acetylation associated with both pre-clinical and FDA-approved KDACi used in the clinic. This report examines a critical reader of DNA methylation and has important implications for understanding MeCP2 regulation in cancer models and identifying novel molecular targets associated with epigenetic therapies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification of Novel MeCP2 Cancer-Associated Target Genes and Post-Translational Modifications

et al. 2020

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“…Mechanistically, LINC00263 increases CAPN2 expression by functioning as a ceRNA of miR-147a, and thus potentiates malignant capabilities. CAPN2 is a calcium-dependent protease that is highly upregulated in various cancers (32). CAPN2 is known to play an important role in proliferation and metastasis of cancer cells (33), and it was also reported to function as an oncogene by inducing EMT and increasing expression of matrix metalloproteinase 9 (MMP9) (32, 34).…”

Section: Discussionmentioning

confidence: 99%

hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2

Lee

Shin

et al. 2020

Preprint

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Background: Malignant characteristics of cancers, represented by rapid cell proliferation and high metastatic potential, are a major cause of high cancer-related mortality. As a multifunctional RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) is closely associated with cancer progression in various types of cancers. In this study, we sought to identify hnRNPK-regulated long intergenic non-coding RNAs (lincRNAs) that play a critical role in the regulation of cancer malignancy.Methods: Malignant phenotypes including metastatic and proliferative potential were examined using Transwell invasion assay, cell counting, and colony forming assay. To search for hnRNPK-regulated lincRNAs, RNA sequencing was performed. Using small RNA sequencing followed by antisense oligonucleotide pull-down, lincRNA-associated miRNAs were selected. The association between miRNA and target mRNA was determined by Argonaute 2-immunoprecipitation and luciferase reporter assay. Results: We found that hnRNPK controlled malignant phenotypes including invasiveness, proliferation, and clonogenicity. RNA sequencing and functional studies revealed that LINC00263, a novel target of hnRNPK, is involved in the oncogenic functions of hnRNPK. Knockdown of LINC00263 mitigated the malignant capabilities. Conversely, increased malignant phenotypes were observed in LINC00263-overexpressing cells. We also found that miR-147a negatively regulates LINC00263 via direct interaction, thus suppressing malignant capabilities. Moreover, knockdown of hnRNPK and LINC00263 upregulated miR-147a, indicating that LINC00263 serves as a ceRNA for miR-147a. By analyzing RNA sequencing data and miRNA target prediction, calpain 2 (CAPN2) was identified as a putative target of miR-147a. Ago2-IP and luciferase reporter assay revealed that miR-147a suppressed CAPN2 expression by directly binding to the 3'UTR of CAPN2 mRNA. Additionally, we found that the weakened malignant capabilities following knockdown of hnRNPK or LINC00263 were restored by miR-147a inhibition or CAPN2 overexpression.Conclusions: Our findings demonstrate that hnRNPK-regulated LINC00263 plays an important role in cancer malignancy by acting as a miR-147a decoy and thus upregulating CAPN2.

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“…Targeted EGFR drugs, such as gefitinib, appear to be effective for approximately 1 year, but resistance is inevitably developed shortly after this period. CAPN2 has been demonstrated to serve a role in altering the cellular response to certain cancer therapies ( 9 , 10 , 19 ). However, the events and mechanisms involved in these processes remain incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

Calpain 2 knockdown promotes cell apoptosis and restores gefitinib sensitivity through epidermal growth factor receptor/protein kinase�B/survivin signaling

et al. 2018

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Gefitinib, an epidermal growth factor receptor (EGFR)-specific drug, is effective for ~1 year, after which resistance is inevitable. Calpain 2 (CAPN2) is known to serve a role in the drug response and resistance in certain cancer therapies. However, the full function of CAPN2, particularly in non-small cell lung cancer, has not yet been elucidated. In the present study, CAPN2 expression in gefitinib-resistant lung adenocarcinoma cells was investigated. CAPN2 function in these cells was further evaluated using gene knockdown both in vitro and in vivo. The results demonstrated that CAPN2 was strongly associated with gefitinib-resistance, and CAPN2 mRNA and protein expression levels were significantly increased in gefitinib-resistant cell lines. Furthermore, CAPN2 knockdown inhibited gefitinib-resistant cell proliferation in vitro and in vivo. CAPN2 conferred gefitinib-resistance by inhibiting cell apoptosis and arresting the cell cycle. CAPN2 knockdown also induced caspase activation and mitochondrial dysfunction, and its function in gefitinib resistance appeared to be largely mediated by EGFR/protein kinase B/survivin signaling pathway activation. These results suggest that CAPN2 is responsible for EGFR-tyrosine kinase inhibitor resistance, and CAPN2 inhibition may be used to provide therapeutic benefits in the treatment of gefitinib resistance.

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Overexpression of CAPN2 promotes cell metastasis and proliferation via AKT/mTOR signaling in renal cell carcinoma

Cited by 21 publications

References 37 publications

Identification of Novel MeCP2 Cancer-Associated Target Genes and Post-Translational Modifications

Identification of Novel MeCP2 Cancer-Associated Target Genes and Post-Translational Modifications

hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2

Calpain 2 knockdown promotes cell apoptosis and restores gefitinib sensitivity through epidermal growth factor receptor/protein kinase�B/survivin signaling

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