Sam68 is required for the growth and survival of nonmelanoma skin cancer

Fu, Kai; Sun, Xin; Xia, Xue; Hobbs, Ryan P.; Guo, Yajuan; Wan, Fengyi

doi:10.1002/cam4.2513

Cited by 9 publications

(8 citation statements)

References 34 publications

(56 reference statements)

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“…SAM68 is known to play important roles in the regulation of mRNA processing, signal transduction, gene transcription, and DNA repair [ 33 , 54 ], and emerging evidence links SAM68 to pathogenic mechanisms, including cell proliferation, apoptosis, invasion, and metastasis in various human cancers [ 55 , 56 , 57 , 58 ]. Previous studies and our data here agree in that upregulation of SAM68 expression is associated with lung cancer progression and poor patient outcome [ 37 , 39 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative O-GlcNAc Proteomic Analysis Reveals a Role of O-GlcNAcylated SAM68 in Lung Cancer Aggressiveness

Lin

Liao

Wang

et al. 2022

Cancers

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O-GlcNAcylation is a reversible and dynamic post-translational protein modification catalyzed by O-GlcNAc transferase (OGT). Despite the reported association of O-GlcNAcylation with cancer metastasis, the O-GlcNAc proteome profile for cancer aggressiveness remains largely uncharacterized. Here, we report our comparative O-GlcNAc proteome profiling of two differentially invasive lung adenocarcinoma cell lines, which identified 158 down-regulated and 106 up-regulated candidates in highly invasive cells. Among these differential proteins, a nuclear RNA-binding protein, SAM68 (SRC associated in mitosis of 68 kDa), was further investigated. Results showed that SAM68 is O-GlcNAcylated and may interact with OGT in the nucleus. Eleven O-GlcNAcylation sites were identified, and data from mutant analysis suggested that multiple serine residues in the N-terminal region are important for O-GlcNAcylation and the function of SAM68 in modulating cancer cell migration and invasion. Analysis of clinical specimens found that high SAM68 expression was associated with late cancer stages, and patients with high-OGT/high-SAM68 expression in their tumors had poorer overall survival compared to those with low-OGT/low-SAM68 expression. Our study revealed an invasiveness-associated O-GlcNAc proteome profile and connected O-GlcNAcylated SAM68 to lung cancer aggressiveness.

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Section: Discussionmentioning

confidence: 99%

Comparative O-GlcNAc Proteomic Analysis Reveals a Role of O-GlcNAcylated SAM68 in Lung Cancer Aggressiveness

Lin

Liao

Wang

et al. 2022

Cancers

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“…Moreover, the Sam68/PARP1 interaction is crucial for DNA damage-initiated, PARP1-dependent PARylation [ 42 ]. T61 resides in the N-terminal region of Sam68 ( Figure 3 A), which is required for the interaction with PARP1 and the downstream activation of NFκB upon DDR induction [ 42 , 53 ]. Thus, we asked if ATM-dependent phosphorylation of T61 could selectively regulate the Sam68–PARP1–NFκB axis.…”

Section: Resultsmentioning

confidence: 99%

“…However, the mechanism involved in this protective function was not elucidated. Subsequent studies in other cellular systems revealed a crucial role for Sam68 in promoting PARP1 recruitment to DNA lesions and NF-κB activation in response to genotoxic stress [ 42 , 43 , 44 , 53 ]. These studies indicated that the N-terminus of Sam68 (aa 1-101) is crucial for the interaction with PARP1 and that this interaction potentiated DDR induction.…”

Section: Discussionmentioning

confidence: 99%

DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation

Stagni

Orecchia

Mignini

et al. 2022

Cancers

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Cancer cells frequently exhibit dysregulation of the DNA damage response (DDR), genomic instability, and altered RNA metabolism. Recent genome-wide studies have strongly suggested an interaction between the pathways involved in the cellular response to DDR and in the regulation of RNA metabolism, but the molecular mechanism(s) involved in this crosstalk are largely unknown. Herein, we found that activation of the DDR kinase ATM promotes its interaction with Sam68, leading to phosphorylation of this multifunctional RNA binding protein (RBP) on three residues: threonine 61, serine 388 and serine 390. Moreover, we demonstrate that ATM-dependent phosphorylation of threonine 61 promotes the function of Sam68 in the DDR pathway and enhances its RNA processing activity. Importantly, ATM-mediated phosphorylation of Sam68 in prostate cancer cells modulates alternative polyadenylation of transcripts that are targets of Sam68, supporting the notion that the ATM–Sam68 axis exerts a multifaceted role in the response to DNA damage. Thus, our work validates Sam68 as an ATM kinase substrate and uncovers an unexpected bidirectional interplay between ATM and Sam68, which couples the DDR pathway to modulation of RNA metabolism in response to genotoxic stress.

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“…SAM68 can also promote polarization movements and cell migration independent of its RNA-binding activity (195). The positive role of SAM68 in tumor transformation has been demonstrated in other types of human cancer (196)(197)(198). It has been demonstrated that SAM68-deficient cells exhibit intron 5 retention in mTOR mRNA, resulting in an early termination codon and a reduction in the mTOR protein levels (199).…”

Section: Sam68mentioning

confidence: 99%

Research progress on RNA‑binding proteins in breast cancer (Review)

et al. 2022

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Breast cancer is the most common malignancy among women, and the abnormal regulation of gene expression serves an important role in its occurrence and development. However, the molecular mechanisms underlying gene expression are highly complex and heterogeneous, and RNA-binding proteins (RBPs) are among the key regulatory factors. RBPs bind targets in an environment-dependent or environment-independent manner to influence mRNA stability and the translation of genes involved in the formation, progression, metastasis and treatment of breast cancer. Due to the growing interest in these regulators, the present review summarizes the most influential studies concerning RBPs associated with breast cancer to elucidate the role of RBPs in breast cancer and to assess how they interact with other key pathways to provide new molecular targets for the diagnosis and treatment of breast cancer.

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Sam68 is required for the growth and survival of nonmelanoma skin cancer

Cited by 9 publications

References 34 publications

Comparative O-GlcNAc Proteomic Analysis Reveals a Role of O-GlcNAcylated SAM68 in Lung Cancer Aggressiveness

Comparative O-GlcNAc Proteomic Analysis Reveals a Role of O-GlcNAcylated SAM68 in Lung Cancer Aggressiveness

DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation

Research progress on RNA‑binding proteins in breast cancer (Review)

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