Proteome dynamics analysis identifies functional roles of SDE2 and hypoxia in DNA damage response in prostate cancer cells

Luo, Ang; Gong, Yao; Kim, Hyungjin; Chen, Yue

doi:10.1093/narcan/zcaa010

Cited by 8 publications

(7 citation statements)

References 54 publications

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“…Nearly 20 years ago, Koshiji et al demonstrated that HIF-1α-rather than other hypoxia-associated genes-that induces the cell cycle arrest [75], which was further confirmed in several genomic and proteomic [31,74,76,77] studies. Cessation of the cell cycle in lymphoma cells was also confirmed in the present work.…”

Section: Discussionmentioning

confidence: 88%

Proteomic-Based Analysis of Hypoxia- and Physioxia-Responsive Proteins and Pathways in Diffuse Large B-Cell Lymphoma

Duś‐Szachniewicz

Gdesz-Birula

Zduniak

et al. 2021

Cells

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Hypoxia is a common feature in most tumors, including hematological malignancies. There is a lack of studies on hypoxia- and physioxia-induced global proteome changes in lymphoma. Here, we sought to explore how the proteome of diffuse large B-cell lymphoma (DLBCL) changes when cells are exposed to acute hypoxic stress (1% of O2) and physioxia (5% of O2) for a long-time. A total of 8239 proteins were identified by LC–MS/MS, of which 718, 513, and 486 had significant changes, in abundance, in the Ri-1, U2904, and U2932 cell lines, respectively. We observed that changes in B-NHL proteome profiles induced by hypoxia and physioxia were quantitatively similar in each cell line; however, differentially abundant proteins (DAPs) were specific to a certain cell line. A significant downregulation of several ribosome proteins indicated a translational inhibition of new ribosome protein synthesis in hypoxia, what was confirmed in a pathway enrichment analysis. In addition, downregulated proteins highlighted the altered cell cycle, metabolism, and interferon signaling. As expected, the enrichment of upregulated proteins revealed terms related to metabolism, HIF1 signaling, and response to oxidative stress. In accordance to our results, physioxia induced weaker changes in the protein abundance when compared to those induced by hypoxia. Our data provide new evidence for understanding mechanisms by which DLBCL cells respond to a variable oxygen level. Furthermore, this study reveals multiple hypoxia-responsive proteins showing an altered abundance in hypoxic and physioxic DLBCL. It remains to be investigated whether changes in the proteomes of DLBCL under normoxia and physioxia have functional consequences on lymphoma development and progression.

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Section: Discussionmentioning

confidence: 88%

Proteomic-Based Analysis of Hypoxia- and Physioxia-Responsive Proteins and Pathways in Diffuse Large B-Cell Lymphoma

Duś‐Szachniewicz

Gdesz-Birula

Zduniak

et al. 2021

Cells

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“…Also, they could function beyond pre-mRNA splicing. Sde2, for example, is reported to regulate the replication stress response ( 21 , 31 , 66 , 67 ) and ribosome biogenesis in humans ( 20 ) and anthocyanin biosynthesis in Arabidopsis ( 68 ).…”

Section: Discussionmentioning

confidence: 99%

Splicing of branchpoint-distant exons is promoted by Cactin, Tls1 and the ubiquitin-fold-activated Sde2

Anil

Choudhary

Pandian

et al. 2022

Nucleic Acids Research

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Intron diversity facilitates regulated gene expression and alternative splicing. Spliceosomes excise introns after recognizing their splicing signals: the 5′-splice site (5′ss), branchpoint (BP) and 3′-splice site (3′ss). The latter two signals are recognized by U2 small nuclear ribonucleoprotein (snRNP) and its accessory factors (U2AFs), but longer spacings between them result in weaker splicing. Here, we show that excision of introns with a BP-distant 3′ss (e.g. rap1 intron 2) requires the ubiquitin-fold-activated splicing regulator Sde2 in Schizosaccharomyces pombe. By monitoring splicing-specific ura4 reporters in a collection of S. pombe mutants, Cay1 and Tls1 were identified as additional regulators of this process. The role of Sde2, Cay1 and Tls1 was further confirmed by increasing BP–3′ss spacings in a canonical tho5 intron. We also examined BP-distant exons spliced independently of these factors and observed that RNA secondary structures possibly bridged the gap between the two signals. These proteins may guide the 3′ss towards the spliceosome's catalytic centre by folding the RNA between the BP and 3′ss. Orthologues of Sde2, Cay1 and Tls1, although missing in the intron-poor Saccharomyces cerevisiae, are present in intron-rich eukaryotes, including humans. This type of intron-specific pre-mRNA splicing appears to have evolved for regulated gene expression and alternative splicing of key heterochromatin factors.

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“…Previous research has indicated the role of these SFs in the development, progression, and prognosis of multiple tumors. [45][46][47][48][49] For example, EIF3A plays a pivotal role in the phenotype and prognosis of bladder cancer by affecting the transcriptome. 49 However, the roles of several other SFs in bladder cancer have not been discussed in previous studies.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapeutic Significance of a Prognostic Alternative Splicing Signature in Bladder Cancer

Chen

Liao

et al. 2022

Technol Cancer Res Treat

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Objectives: Bladder cancer is the fourth most common malignancy in men in the United States. Aberrant alternative splicing (AS) events are involved in the carcinogenesis, but the association between AS and bladder cancer remains unclear. This study aimed to construct an AS-based prognostic signature and elucidate the role of the tumor immune microenvironment (TIME) and the response to immunotherapy and chemotherapy in bladder cancer. Methods: Univariate Cox regression analysis was performed to detect prognosis-related AS events. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox analyses were employed to build prognostic signatures. Kaplan–Meier survival analysis, multivariate Cox regression analysis, and receiver operating characteristic (ROC) curves were conducted to validate the prognostic signatures. Then, the Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) and tumor immune estimation resource (TIMER) databases were searched and the single-sample gene set enrichment analysis (ssGSEA) algorithm and CIBERSORT method were performed to uncover the context of TIME in bladder cancer. The Tumor Immune Dysfunction and Exclusion (TIDE) web tool and pRRophetic algorithm were used to predict the response to immunotherapy and chemotherapy. Finally, we constructed a correlation network between splicing factors (SFs) and survival-related AS events. Results: A total of 4684 AS events were significantly associated with overall survival in patients with bladder cancer. Eight prognostic signatures of bladder cancer were established, and a clinical survival prediction model was built. In addition, the consolidated prognostic signature was closely related to immune infiltration and the response to immunotherapy and chemotherapy. Furthermore, the correlation identified EIF3A, DDX21, SDE2, TNPO1, and RNF40 as hub SFs, and function analysis found ubiquitin-mediated proteolysis is correlated most significantly with survival-associated AS events. Conclusion: Our findings highlight the prognostic value of AS for patients with bladder cancer and reveal pivotal players of AS events in the context of TIME and the response to immunotherapy and chemotherapy, which may be important for patient management and treatment.

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Proteome dynamics analysis identifies functional roles of SDE2 and hypoxia in DNA damage response in prostate cancer cells

Cited by 8 publications

References 54 publications

Proteomic-Based Analysis of Hypoxia- and Physioxia-Responsive Proteins and Pathways in Diffuse Large B-Cell Lymphoma

Proteomic-Based Analysis of Hypoxia- and Physioxia-Responsive Proteins and Pathways in Diffuse Large B-Cell Lymphoma

Splicing of branchpoint-distant exons is promoted by Cactin, Tls1 and the ubiquitin-fold-activated Sde2

Immunotherapeutic Significance of a Prognostic Alternative Splicing Signature in Bladder Cancer

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