Inhibiting β-catenin disables nucleolar functions in triple-negative breast cancer

Weeks, Shannon E.; Kammerud, Sarah C.; Metge, Brandon J.; Alsheikh, Heba Allah; Schneider, David A.; Chen, Dongquan; Wei, Shi; Mobley, James A.; Ojesina, Akinyemi I.; Shevde, Lalita A.; Samant, Rajeev S.

doi:10.1038/s41419-021-03531-z

Cited by 17 publications

(16 citation statements)

References 47 publications

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“…For instance, Dr. Vincent’s studies show that the induction of ribosome biogenesis is a general feature of the EMT program and can promote the cellular plasticity and migration ( 42 ). Similarly, except for contributing to the ribosomal biogenesis, LAS1L has also been reported to be involved in tumor cell proliferation ( 18 ), metastasis ( 20 ) and autophagy ( 19 ). Among them, Dr. Samant ‘s research shows that knockdown of LAS1L leads to a sharp reduction in tumorigenic and metastatic properties in triple-negative breast cancer ( 20 ), which is similar to Dr. Vincent’s conclusion.…”

Section: Discussionmentioning

confidence: 99%

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Knockdown of hnRNPA1 Promotes NSCLC Metastasis and EMT by Regulating Alternative Splicing of LAS1L exon 9

et al. 2022

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Tumor metastasis is still an insurmountable obstacle in tumor treatment. Lung cancer represents one of the most common malignancies with high morbidity worldwide. hnRNPA1 has been reported to be involved in the regulation of tumor metastasis, while its specific role in tumor metastasis seems to be controversial and its molecular mechanism in lung cancer metastasis remains to be further elucidated. In this study, we confirmed that knockdown of the hnRNPA1 led to enhanced migration, invasion and EMT transition in lung cancer cells. Bioinformatics analysis of the GSE34992 dataset revealed that hnRNPA1 may regulate the alternative splicing (AS) of LAS1L exon 9. Further AGE assays and RIP assays revealed that hnRNPA1 can directly bind to the LAS1L pre-mRNA to inhibit the splicing of LAS1L exon 9. The RNA pull-down assays showed that hnRNPA1 can specifically bind to the two sites (UAGGGU(WT1) and UGGGGU(WT3)) of LAS1L Intron 9. Further Transwell assays indicated that the expression ratio of LAS1L-L/LAS1L-S regulated by hnRNPA1 can further promote the migration, invasion and EMT transition in lung cancer cells. Moreover, hnRNPA1 expression showed significant heterogeneity in lung cancer tissues, which may contain new research directions and potential therapeutic targets. Our results indicate that hnRNPA1 can affect the metastasis of lung cancer cells by modulating the AS of LAS1L exon 9, highlighting the potential significance of hnRNPA1 in lung cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

“…The crucial role of LAS1L in tumor progression is being revealed. A recent study from Dr. Samant also showed that knockdown of LAS1L leads to a reduction in proliferation and metastatic potential of triple negative breast cancer cells (20). However, studies on the AS regulation of LAS1L in tumor have not been reported.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of hnRNPA1 Promotes NSCLC Metastasis and EMT by Regulating Alternative Splicing of LAS1L exon 9

et al. 2022

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“…Dyskerin is an essential nucleolar protein that can affect the growth of tumors through its related mechanism of rRNA processing in the precursor (33); the rRNA synthesis inhibitor CX-5461 can induce acute lymphocytes by activating the ATM/ATR pathway, leukemia cells stagnate and die (34). The growth of triple-negative breast cancer requires high-demand ribosome biosynthesis (35); ribosome biogenesis can affect the biological behavior of cell senescence and cancer through a connection with the target of the rapamycin (TOR) signaling pathway (36). The above evidence indicates that RRP12 can also affect the occurrence and development of tumors by affecting the synthesis and metabolism of ribosomes.…”

Section: Discussionmentioning

confidence: 99%

Validating RRP12 Expression and Its Prognostic Significance in HCC Based on Data Mining and Bioinformatics Methods

et al. 2022

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RRP12 (ribosomal RNA processing 12 homolog) is a nucleolar protein involved in the maturation and transport of eukaryotic ribosomal subunits and is a type of RNA binding protein. In recent years, considerable research has indicated that RRP12 is associated with the occurrence and development of multiple cancers. However, there is no research on RRP12 in hepatocellular carcinoma. Herein, we aimed to explore the role and significance of RRP12 in hepatocellular carcinoma.We used the TIMER and GEPIA databases to perform pan-cancer analyses of RRP12. The impact of RRP12 on the prognosis was analyzed through the GEPIA database. The relationship between RRP12 and immune cell infiltration was investigated by TIMER and GEPIA databases. Moreover, the expression of RRP12 in various liver cancer cells was evaluated by Western Blot to determine the cell line for the next experiment. Scratch test, Transwell test, and Edu tests were applied to validate the effects of RRP12 on the function of liver cancer cells. And the data were statistically analyzed.Pan-cancer analysis found that RPP12 was significantly upregulated in many cancers. Moreover, the prognostic analysis revealed that the difference in the expression of RRP12 has statistical significance for the overall survival rate and disease-free survival rate of liver cancer patients. In order to analyze the correlation between the expression level of RRP12 and clinical parameters, it was found that there was a significant negative correlation with tumor stage, tumor grade and tumor size. Univariate and multivariate analysis showed that RRP12 could be used as an independent prognostic factor for patients with hepatocellular carcinoma. Cellular experiments have proved that knocking down RRP12 can inhibit the proliferation, invasion, and metastasis of liver cancer cells.Therefore, RRP12 significantly affects the occurrence and development of HCC. Hence, RRP12 can become a potential target and prognostic biomarker for the treatment of hepatocellular carcinoma.

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“…Sustained elevated ribosome biogenesis is one of the classical hallmarks of aberrant cell growth. With its distinct pathological features in malignant cells, the nucleolus has attracted recent attention as a novel drug target [ 31 , 69 , 70 ]. Many structurally diverse molecules have been reported to directly or indirectly perturb the dynamic functionality of the nucleolus [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

“…We recently demonstrated that triple-negative breast cancer (TNBC) cells are more reliant on elevated rRNA biogenesis [ 31 ]. Thus, in this study, we use two human TNBCs, SUM159 and MDA-MB-468, and one metastatic murine mammary cancer cell line 4T1.…”

Section: Methodsmentioning

confidence: 99%

Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis

Kammerud

Metge

Elhamamsy

et al. 2021

Laboratory Investigation

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The nucleolus of a cell is a critical cellular compartment that is responsible for ribosome biogenesis and plays a central role in tumor progression. Fisetin, a nutraceutical, is a naturally occurring flavonol from the flavonoid group of polyphenols that has anti-cancer effects. Fisetin negatively impacts several signaling pathways that support tumor progression. However, effect of fisetin on the nucleolus and its functions were unknown. We observed that fisetin is able to physically enter the nucleolus. In the nucleolus, RNA polymerase I (RNA Pol I) mediates the biogenesis of ribosomal RNA. Thus, we investigated the impacts of fisetin on the nucleolus. We observed that breast tumor cells treated with fisetin show a 20–30% decreased nucleolar abundance per cell and a 30–60% downregulation of RNA Pol I transcription activity, as well as a 50–70% reduction in nascent rRNA synthesis, depending on the cell line. Our studies show that fisetin negatively influences MAPK/ERK pathway to impair RNA Pol I activity and rRNA biogenesis. Functionally, we demonstrate that fisetin acts synergistically (CI = 0.4) with RNA Pol I inhibitor, BMH-21 and shows a noteworthy negative impact (60% decrease) on lung colonization of breast cancer cells. Overall, our findings highlight the potential of ribosomal RNA (rRNA) biogenesis as a target for secondary prevention and possible treatment of metastatic disease.

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Inhibiting β-catenin disables nucleolar functions in triple-negative breast cancer

Cited by 17 publications

References 47 publications

Knockdown of hnRNPA1 Promotes NSCLC Metastasis and EMT by Regulating Alternative Splicing of LAS1L exon 9

Knockdown of hnRNPA1 Promotes NSCLC Metastasis and EMT by Regulating Alternative Splicing of LAS1L exon 9

Validating RRP12 Expression and Its Prognostic Significance in HCC Based on Data Mining and Bioinformatics Methods

Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis

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