Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention

Koedoot, Esmee; Steijn, Eline van; Vermeer, Marjolein; González-Prieto, Román; Vertegaal, Alfred C.O.; Martens, John W.M.; Dévédec, Sylvia E. Le; Water, Bob van de

doi:10.1186/s13046-021-01863-4

Cited by 26 publications

(26 citation statements)

References 48 publications

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“…It has been found to have a regulatory effect on p53 expression in non-small cell lung cancer. It also has a role in triple-negative breast cancer cell proliferation [26,29]. In our model we found EXOC9 to be highly correlated with FRG1 in multiple cancer types.…”

Section: Discussionmentioning

confidence: 72%

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

Khan

Palo

Dixit

2021

Preprint

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FRG1 has a role in tumorigenesis and angiogenesis. Our preliminary analysis showed FRG1 expression is associated with the overall survival (OS) in cancers the effect varies. In cervix and gastric cancers, we found a clear difference in the OS between the low and high FRG1 expression groups, but in breast, lung, and liver cancers the difference was not prominent. We hypothesized that the functionality of the genes correlated with FRG1 could be getting affected by FRG1 or vice versa, which might mask the effect of a single gene on the OS analysis in cancer patients. We used the multivariate Cox regression, risk score, and Kaplan Meier analyses to determine OS in a multigene model. STRING, Cytoscape, and HIPPIE were used to deduce FRG1 associated pathways. In breast, lung, and liver cancer we found a distinct difference in the OS, between the low and high FRG1 expression groups in the multigene model, suggesting an independent role of FRG1 in survival. Risk scores were calculated based upon regression coefficients in the multigene model. Low and high-risk score groups revealed a significant difference in the FRG1 expression and survival. HPF1, RPL34, and EXOSC9 were the most common genes present in FRG1 associated pathways across the cancer types. Validation of the effect of FRG1 expression on these genes by qRT-PCR, supports that FRG1 might be an upstream regulator of their expression. These genes may have multiple regulators which also affect their expression, leading to the masking effect in the survival analysis. In conclusion, our study highlights the role of FRG1 in the survivability of cancer patients in tissue-specific manner and the use of multigene models in prognosis.

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Section: Discussionmentioning

confidence: 72%

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

Khan

Palo

Dixit

2021

Preprint

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“… 50 Additionally, aberrant splicing of the pre-mRNA coding for sororin, the regulator of sister chromatid cohesion, in cells depleted in SNRPD3 might be a key factor affecting mitosis in triple-negative breast cancer cells. 51 Considering the key role of SNRPD3 in splicing, many transcripts, including those encoding proteins important for cell survival and proliferation, are probably affected by incorrect alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

Non-targeting control for MISSION shRNA library silences SNRPD3 leading to cell death or permanent growth arrest

Czarnek

Sarad

Karaś

et al. 2021

Molecular Therapy - Nucleic Acids

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In parallel with the expansion of RNA interference (RNAi) techniques, accumulating evidence indicates that RNAi analyses might be seriously biased due to the off-target effects of gene-specific short hairpin RNAs (shRNAs). Our findings indicated that off-target effects of non-targeting shRNA comprise another source of misinterpreted shRNA-based data. We found that SHC016, which is one of two non-targeting shRNA controls for the MISSION (commercialized TRC) library, exerts deleterious effects that lead to elimination of the shRNA-coding cassette from the genomes of cultured murine and human cells. Here, we used a lentiviral vector with inducible SHC016 expression to confirm that this shRNA induces apoptosis in murine cells and senescence or mitotic catastrophe depending on the p53 status in human tumor cells. We identified the core spliceosomal protein, small nuclear ribonucleoprotein Sm D3 (SNRPD3), as a major SHC016 target in several cell lines and confirmed that CRISPRi knockdown of SNRPD3 mimics the effects of SHC016 expression in A549 and U251 cells. The overexpression of SNRPD3 rescued U251 cells from SHC016-induced mitotic catastrophe. Our findings disqualified non-targeting SHC016 shRNA and added a new premise to the discussion about the sources of uncertainty in RNAi results.

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“…It has been found to have a regulatory effect on p53 expression in non-small cell lung cancer. It also has a role in triple-negative breast cancer cell proliferation 38 , 41 . In our model we found EXOSC9 to be highly correlated with FRG1 in multiple cancer types.…”

Section: Discussionmentioning

confidence: 99%

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

Khan

Palo

Dixit

2021

Sci Rep

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FRG1 has a role in tumorigenesis and angiogenesis. Our preliminary analysis showed that FRG1 mRNA expression is associated with overall survival (OS) in certain cancers, but the effect varies. In cervix and gastric cancers, we found a clear difference in the OS between the low and high FRG1 mRNA expression groups, but the difference was not prominent in breast, lung, and liver cancers. We hypothesized that FRG1 expression level could affect the functionality of the correlated genes or vice versa, which might mask the effect of a single gene on the OS analysis in cancer patients. We used the multivariate Cox regression, risk score, and Kaplan Meier analyses to determine OS in a multigene model. STRING, Cytoscape, HIPPIE, Gene Ontology, and DAVID (KEGG) were used to deduce FRG1 associated pathways. In breast, lung, and liver cancers, we found a distinct difference in the OS between the low and high FRG1 mRNA expression groups in the multigene model, suggesting an independent role of FRG1 in survival. Risk scores were calculated based upon regression coefficients in the multigene model. Low and high-risk score groups showed a significant difference in the FRG1 mRNA expression level and OS. HPF1, RPL34, and EXOSC9 were the most common genes present in FRG1 associated pathways across the cancer types. Validation of the effect of FRG1 mRNA expression level on these genes by qRT-PCR supports that FRG1 might be an upstream regulator of their expression. These genes may have multiple regulators, which also affect their expression, leading to the masking effect in the survival analysis. In conclusion, our study highlights the role of FRG1 in the survivability of cancer patients in tissue-specific manner and the use of multigene models in prognosis.

show abstract

Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention

Cited by 26 publications

References 48 publications

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

Non-targeting control for MISSION shRNA library silences SNRPD3 leading to cell death or permanent growth arrest

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

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