Inactivation of homeodomain‐interacting protein kinase 2 promotes oral squamous cell carcinoma metastasis through inhibition of P53‐dependent E‐cadherin expression

Zheng, Xueqing; Pan, Yifan; Chen, Xinming; Xia, Sun-Hui; Hu, Yaying; Zhou, Yi; Zhang, Jiali

doi:10.1111/cas.14691

Cited by 9 publications

(5 citation statements)

References 52 publications

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“…For instance, HIPK2 is expressed at low levels in oral squamous cell carcinoma, and low expression of HIPK2 promotes the invasion of tumour cells and metastasis of cervical lymph nodes. Mechanistically, E-cadherin expression is triggered by mediating P53, which directly targets the CDH1 (encoding E-cadherin) promoter[ 32 ]. In colorectal cancer, the percentage of HIPK2-positive cells increases with tumour progression, is significantly associated with tumour lymph node metastasis stage and is associated with worse prognosis.…”

Section: Discussionmentioning

confidence: 99%

Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription

Li,

Yang,

Wang

et al. 2024

World J Gastrointest Oncol

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BACKGROUND Colorectal cancer (CRC) is the third most common cancer and a significant cause of cancer-related mortality globally. Resistance to chemotherapy, especially during CRC treatment, leads to reduced effectiveness of drugs and poor patient outcomes. Long noncoding RNAs (lncRNAs) have been implicated in various pathophysiological processes of tumor cells, including chemotherapy resistance, yet the roles of many lncRNAs in CRC remain unclear. AIM To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance. METHODS Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance. Various bioinformatics tools were employed to elucidate molecular mechanisms. The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction. Functional assays, including MTT, wound healing, and Transwell, were conducted to investigate the functional implications of lncRNA alterations. Interactions between lncRNAs and transcription factors were examined using RIP and luciferase reporter assays, while Western blotting was used to confirm downstream pathways. Additionally, a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance. RESULTS LncRNA prion protein testis specific (PRNT) was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2 (HIPK2) expression. PRNT was demonstrated to sponge transcription factor zinc finger protein 184 (ZNF184), which in turn could regulate HIPK2 expression. Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin, with overexpression leading to decreased sensitivity and decreased expression reducing resistance. Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT. The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo . CONCLUSION The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184. This regulatory mechanism enhances CRC progression and resistance to oxaliplatin, positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription

Li,

Yang,

Wang

et al. 2024

World J Gastrointest Oncol

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“…In lung cancer, HIPK2 was downregulated in tumor tissues and its suppression enhanced cell metastasis 25 . Depletion of HIPK2 expression had been shown to promote oral squamous cell carcinoma cell metastasis 26 . It had been reported that LINC00261 repressed pancreatic cancer glycolysis and growth by increasing HIPK2 level via targeting miR-222-3p 27 .…”

Section: Discussionmentioning

confidence: 99%

Exosome-transmitted hsa_circ_0012634 suppresses pancreatic ductal adenocarcinoma progression through regulating miR-147b/HIPK2 axis

Wang

Ruan

et al. 2023

Cancer Biology & Therapy

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Circular RNA (circRNA) has been confirmed to play a vital role in pancreatic ductal adenocarcinoma (PDAC) progression. However, the function and regulatory mechanism of hsa_circ_0012634 in PDAC progression remain unclear. Quantitative real-time PCR was used to measure the expression of hsa_circ_0012634, microRNA (miR)-147b and homeodomain interacting protein kinase 2 (HIPK2). Cell function was assessed by cell counting kit 8 assay, EdU assay, colony formation assay and flow cytometry. Glucose uptake and lactate production were evaluated to determine cell glycolysis ability. Protein expression was examined by western blot analysis. RNA interaction was confirmed by RNA pull-down assay and dual-luciferase reporter assay. Exosomes were isolated from serums and cell culture supernatant using ultracentrifugation and identified by transmission electron microscopy. Animal experiments were conducted using nude mice. Hsa_circ_0012634 was downregulated in PDAC tissues and cells, and its overexpression suppressed PDAC cell proliferation, glycolysis and enhanced apoptosis. MiR-147b was targeted by hsa_circ_0012634, and its inhibitors repressed PDAC cell growth and glycolysis. HIPK2 could be targeted by miR-147b, and hsa_circ_0012634 regulated miR-147b/HIPK2 to suppress PDAC cell progression. Hsa_circ_0012634 was lowly expressed in serum exosomes of PDAC patients. Exosomal hsa_circ_0012634 inhibited PDAC cell growth and glycolysis in vitro, as well as tumorigenesis in vivo. Exosomal hsa_circ_0012634 restrained PDAC progression via the miR-147b/HIPK2 pathway, confirming that hsa_circ_0012634 might serve as a diagnosis and treatment biomarker for PDAC.

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“…E-cadherin expression is known to be regulated by both transcriptional and post-translational mechanisms [ 12 , 15 ]. In tumor cells, p53 can transcriptionally promote E-cadherin expression by directly targeting the CDH1 (coding E-cadherin) promoter [ 38 ] or indirectly reducing DNMT1-mediated CDH1 promoter methylation [ 10 , 11 ]. However, we found that cisplatin-induced p53 activation led to loss of E-cadherin in RPTCs.…”

Section: Discussionmentioning

confidence: 99%

Histone methyltransferase MLL1 drives renal tubular cell apoptosis by p53-dependent repression of E-cadherin during cisplatin-induced acute kidney injury

et al. 2022

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Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase that interacts with WD repeat domain 5 (WDR5) to regulate cell survival, proliferation, and senescence. The role of MLL1 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we demonstrate that MLL1, WDR5, and trimethylated H3K4 (H3K4me3) were upregulated in renal tubular cells of cisplatin-induced AKI in mice, along with increased phosphorylation of p53 and decreased expression of E-cadherin. Administration of MM102, a selective MLL1/WDR5 complex inhibitor, improved renal function and attenuated tubular injury and apoptosis, while repressing MLL1, WDR5, and H3K4me3, dephosphorylating p53 and preserving E-cadherin. In cultured mouse renal proximal tubular cells (RPTCs) exposed to cisplatin, treatment with MM102 or transfection with siRNAs for either MLL1 or WDR5 also inhibited apoptosis and p53 phosphorylation while preserving E-cadherin expression; p53 inhibition with Pifithrin-α lowered cisplatin-induced apoptosis without affecting expression of MLL1, WDR5, and H3K4me3. Interestingly, silencing of E-cadherin offset MM102’s cytoprotective effects, but had no effect on p53 phosphorylation. These findings suggest that MLL1/WDR5 activates p53, which, in turn, represses E-cadherin, leading to apoptosis during cisplatin-induced AKI. Further studies showed that MM102 effectively inhibited cisplatin-triggered DNA damage response (DDR), as indicated by dephosphorylation of ataxia telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR) proteins, dephosphorylation of checkpoint kinase 1 and 2 (Chk1 and Chk2); depression of γ-H2AX; and restrained cell cycle arrest, as evidenced by decreased expression of p21 and phospho-histone H3 at serine 10 in vitro and in vivo. Overall, we identify MLL1 as a novel DDR regulator that drives cisplatin-induced RPTC apoptosis and AKI by modulating the MLL1/WDR5-/ATR/ATM-Chk-p53-E-cadherin axis. Targeting the MLL1/WDR5 complex may have a therapeutic potential for the treatment of AKI.

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Inactivation of homeodomain‐interacting protein kinase 2 promotes oral squamous cell carcinoma metastasis through inhibition of P53‐dependent E‐cadherin expression

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 9 publications

References 52 publications

Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription

Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription

Exosome-transmitted hsa_circ_0012634 suppresses pancreatic ductal adenocarcinoma progression through regulating miR-147b/HIPK2 axis

Histone methyltransferase MLL1 drives renal tubular cell apoptosis by p53-dependent repression of E-cadherin during cisplatin-induced acute kidney injury

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