Coupling function of cyclin‐dependent kinase 2 and Septin2 in the promotion of hepatocellular carcinoma

Xu, Chenzhou; Zhang, Wei; Zhang, Xuening; Zhou, Danhua; Qu, Lei; Liu, Jinxia; Xiao, Mingbing; Ni, Runzhou; Jiang, Feng; Ni, Wenkai; Lu, Cuihua

doi:10.1111/cas.13882

Cited by 9 publications

(5 citation statements)

References 30 publications

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“…Septin 7 plays a downstream effect in ERK3-induced migration of cancer cells, and its deletion abolishes the ability of ERK3 to promote lung cancer cell migration and invasion [47]. CDK2 interacts with SEPT2 to stabilize SEPT2 in HCC cells, and HCC with high expression of both CDK2 and SEPT2 is more prone to recurrence and may be more aggressive [48]. As a new member of the septin family, we reported the function of SEPT11 in HCC progression for the first time.…”

Section: Discussionmentioning

confidence: 90%

Septin11 promotes hepatocellular carcinoma cell motility by activating RhoA to regulate cytoskeleton and cell adhesion

Wang

Yang

et al. 2023

Cell Death Dis

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Septins as GTPases in the cytoskeleton, are linked to a broad spectrum of cellular functions, including cell migration and the progression of hepatocellular carcinoma (HCC). However, roles of SEPT11, the new member of septin, have been hardly understood in HCC. In the study, the clinical significance and biological function of SEPT11 in HCC was explored. SEPT11 was screened out by combining ATAC-seq with mRNA-seq. Role of SEPT11 in HCC was further investigated by using overexpression, shRNA and CRISPR/Cas9-mediated SEPT11-knockout cells or in vivo models. We found RNA-seq and ATAC-seq highlights LncRNA AY927503 (AY) induced SEPT11 transcription, resulting in Rho GTPase activation and cytoskeleton actin aggregation. The GTP-binding protein SEPT11 is thus considered, as a downstream factor of AY, highly expressed in various tumors, including HCC, and associated with poor prognosis of the patients. In vitro, SEPT11 overexpression promotes the migration and invasion of HCC cells, while SEPT11-knockout inhibits migration and invasion. In vivo, SEPT11-overexpressed HCC cells show high metastasis incidents but don’t significantly affect proliferation. Meanwhile, we found SEPT11 targets RhoA, thereby regulating cytoskeleton rearrangement and abnormal cell adhesion through ROCK1/cofilin and FAK/paxillin signaling pathways, promoting invasion and migration of HCC. Further, we found SEPT11 facilitates the binding of GEF-H1 to RhoA, which enhances the activity of RhoA. Overall, our study confirmed function of SEPT11 in promoting metastasis in HCC, and preliminarily explored its related molecular mechanism. SEPT11 acts as an oncogene in HCC, also draws further interest regarding its clinical application as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 90%

Septin11 promotes hepatocellular carcinoma cell motility by activating RhoA to regulate cytoskeleton and cell adhesion

Wang

Yang

et al. 2023

Cell Death Dis

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“…SEPT2 and its family members are important oncogenes that play roles in the development of various tumours (Bridges and Gladfelter, 2015). For example, high expression of SEPT2 was significantly correlated with tumour differentiation and microvessel infiltration, which was an independent prognostic factor in patients with HCC (Xu et al, 2019). SEPT2 and SEPT9 suppression inhibited glioblastoma cell proliferation, caused S phase cell cycle arrest in a coordinating mechanism, decreased cell invasion and significantly inhibited glioma xenograft growth in nude mice (Xu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle‐derived circ_SLC19A1 promotes prostate cancer cell growth and invasion through the miR‐497/septin 2 pathway

Zheng

Chen

et al. 2020

Cell Biology International

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The occurrence and development of prostate cancer (PCa) is complex, and the related mechanism is not fully understood. Current studies have found that extracellular vesicles (EVs) and circular RNAs (circRNAs) have important functions in various tumours and other diseases. In this study, the detection of circRNAs in PCa showed that circ_SLC19A1 was increased in PCa cells and their secreted EVs. EVs with high expression of circ_SLC19A1 could be taken up by PCa cells, which promoted cell proliferation and invasion. The sequence of circ_SLC19A1 contained multiple binding sites for miR‐497, and circ_SLC19A1 could bind directly to miR‐497 in cells. The expression of miR‐497 was downregulated in PCa cells, while the expression of its target gene septin 2 (SEPT2) was upregulated significantly. Transfection of circ_SLC19A1 small interfering RNA (siRNA) or miR‐497 mimics could significantly inhibit the expression of SEPT2 and the phosphorylation of extracellular signal‐regulated kinase 1 and 2 (ERK1/2). After co‐transfection of circ_SLC19A1 siRNA and miR‐497 inhibitors or SEPT2 overexpression vector, the expression of SEPT2 and ERK1/2 phosphorylation levels showed no significant changes. Similar results were obtained with co‐transfection of miR‐497 mimics and the SEPT2 overexpression vector. Therefore, cancer cells can regulate the expression of SEPT2 through miR‐497 by secreting EVs with high expression of circ_SLC19A1, thus affecting the activation of the downstream ERK1/2 pathway and ultimately regulating PCa cell growth and invasion. Therefore, EV‐derived circ_SLC19A1 plays an important regulatory role in PCa and may be an important target for PCa prevention and treatment.

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“…SEPT2 is crucial in spindle formation and sister chromatid separation, thereby regulating G2/M phase transition and cell mitosis [ 19 ]. Whereas several studies have shown that SEPT2 can facilitate tumor growth and metastasis [ 20 , 21 ]. We identified that the two crotonylation sites in SEPT2, K318 (H/L = 1.3, p < 0.05) and K74 (H/L = 2.19, p < 0.05), were significantly differentially crotonylated, as determined by LS-MS/MS.…”

Section: Resultsmentioning

confidence: 99%

SEPT2 crotonylation promotes metastasis and recurrence in hepatocellular carcinoma and is associated with poor survival

et al. 2023

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Background Hepatocellular carcinoma (HCC) metastasis and recurrence lead to therapy failure, which are closely associated with the proteome. However, the role of post-translational modification (PTM) in HCC, especially for the recently discovered lysine crotonylation (Kcr), is elusive. Results We investigated the correlation between crotonylation and HCC in 100 tumor tissues and performed stable isotope labeling by amino acids and liquid chromatography tandem mass spectrometry in HCC cells, and we found that crotonylation was positively correlated with HCC metastasis, and higher crotonylation in HCC cells facilitated cell invasiveness. Through bioinformatic analysis, we found that the crotonylated protein SEPT2 was significantly hypercrotonylated in highly invasive cells, while the decrotonylated mutation of SEPT2-K74 impaired SEPT2 GTPase activity and inhibited HCC metastasis in vitro and in vivo. Mechanistically, SIRT2 decrotonylated SEPT2, and P85α was found to be the downstream effector of SEPT2. Moreover, we identified that SEPT2-K74cr was correlated with poor prognosis and recurrence in HCC patients, thus indicating its clinical potential as an independent prognostic factor. Conclusions We revealed the role of nonhistone protein crotonylation in regulating HCC metastasis and invasion. Crotonylation facilitated cell invasion through the crotonylated SEPT2-K74-P85α-AKT pathway. High SEPT2-K74 crotonylation predicted poor prognosis and a high recurrence rate in HCC patients. Our study revealed a novel role of crotonylation in promoting HCC metastasis.

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Coupling function of cyclin‐dependent kinase 2 and Septin2 in the promotion of hepatocellular carcinoma

Cited by 9 publications

References 30 publications

Septin11 promotes hepatocellular carcinoma cell motility by activating RhoA to regulate cytoskeleton and cell adhesion

Septin11 promotes hepatocellular carcinoma cell motility by activating RhoA to regulate cytoskeleton and cell adhesion

Extracellular vesicle‐derived circ_SLC19A1 promotes prostate cancer cell growth and invasion through the miR‐497/septin 2 pathway

SEPT2 crotonylation promotes metastasis and recurrence in hepatocellular carcinoma and is associated with poor survival

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