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Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling proteins. Dysfunctions or mutations in LSH causes an autosomal recessive disease known as immunodeficiency-centromeric instability-facial anomaly (ICF) syndrome. Interestingly, LSH participates in various aspects of epigenetic regulation, including nucleosome remodelling, DNA methylation, histone modifications and heterochromatin formation. Further, LSH plays a crucial role during DNA-damage repair, specifically during double-strand break (DSB) repair, since murine LSH was shown to be essential for non-homologous end joining (NHEJ) and homologous recombination (HR). Accordingly, overexpression of LSH drives tumorigenesis and malignancy. On the other hand, LSH homologs stabilise the genome. Thus, LSH might be implemented as a biomarker for various cancer types and potential target molecule to develop therapeutic strategies against them. In this review, we focus on the role of LSH in orchestrating chromatin rearrangements, such as DNA methylation and histone modifications, as well as in DNA-damage repair. Changes in chromatin structure may facilitate gene expression signatures that cause malignant transformation. We summarise recent findings of LSH in cancers and raise critical open questions for further studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Posttranslational modifications (PTMs) of proteins, including chromatin modifiers, play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties. However, the roles of Lymphoid-specific helicase (LSH), a DNA methylation modifier, in modulating stem-like properties in cancer are still not clearly clarified. Therefore, exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH. Here, we demonstrate that LSH is capable to undergo PTMs, including methylation and phosphorylation. The arginine methyltransferase PRMT5 can methylate LSH at R309 residue, meanwhile, LSH could as well be phosphorylated by MAPK1 kinase at S503 residue. We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue, which eventually promoting stem-like properties in lung cancer. Whereas, phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties, indicating the critical roles of LSH PTMs in modulating stem-like properties. Thus, our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.

Elucidating mechanisms in tumor suppressors and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, the interplay between long intergenic non-coding RNAs (lncRNAs) and chromatin remodeling remains unclear. Here, we showed that GIAT4RA, a poorly characterized lncRNA LOC102723729, was significantly decreased in lung cancer cells and tissues; while no association was observed with clinical risk factors, expression was linked with clinical stage and lymphatic metastasis. Higher expression of GIAT4RA was linked with overall survival in NSCLC. GIAT4RA inhibited many characteristics of tumorigenesis including cell growth, clonal formation, migration and invasion, epithelial-mesenchymal transition, tumor sphere and tumor growth in vivo. Mechanistically, GIAT4RA was essential for the degradation of chromatin modifier lymphoid-specific helicase (LSH) by counteracting the deubiquintination in proteasome pathway by binding to 227-589 AA of LSH. GIAT4RA interfered with ubiquitin hydrolase Uchl3-mediated interaction and stabilization of LSH. LSH knockdown rescued GIAT4RA-promoted features, and LSH overexpression prevented GIAT4RA-induced phenotypes. Taken together, lncRNA GIAT4RA plays a critical role in NSCLC adenocarcinoma as a ubiquitination regulator and tumor suppressor.

Background: The stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase MDM2. The chromatin modifier lymphoid-specific helicase (LSH) is essential for DNA methylation and cancer progression as a transcriptional repressor. The potential interplay between chromatin modifiers and transcription factors remains largely unknown., Results: Here, we present data suggesting that LSH regulates p53 in cis through two pathways: prevention proteasomal degradation through its deubiquitination, which is achieved by reducing the lysine 11-linked, lysine 48-linked polyubiquitin chains (K11 and K48) on p53; and revival of the transcriptional activity of p53 by forming a complex with PKM2 (pyruvate kinase 2). Furthermore, we confirmed that the LSH-PKM2 interaction occurred at the intersubunit interface region of the PKM2 C-terminal region and the coiled-coil domains (CC) and ATP-binding domains of LSH, and this interaction regulated p53-mediated transactivation in cis in lipid metabolism, especially lipid catabolism., Conclusion: These findings suggest that LSH is a novel regulator of p53 through the proteasomal pathway, thereby providing an alternative mechanism of p53 involvement in lipid metabolism in cancer.

Background: Elucidating mechanisms in oncogenes and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, regulation of oncogene by chromatin modifiers at post-transcriptional level is critical and remains unclear. We have investigated the role of GINS4 in NSCLC., Methods: The expression of chromatin modifier lymphoid-specific helicase (LSH) and GINS4 was assessed in tumor and normal tissue from 79 patients with NSCLC with clinical characteristics. HBE, A549, H358, and H522, PC9, 95C and 95D were cultured after overexpression or silencing of GIAT4RA. Cell proliferation assay, cell migration and invasion assays, plate colony formation assay, immunofluorescence assay, Operetta® high-content screening and analysis, Western blot analysis and Co-Immunoprecipitation (Co-IP) assay, RNA immunoprecipitation assay and tumor growth assay was used to address the potential interplay of between GINS4 and LSH, and the functional of GINS4., Results: GINS4 is highly expressed in lung cancer cells and tissues, and GINS4 expression is not association with clinical risk factors, but linked with clinical stage and lymphatic metastasis status. Higher expression of GINS4 poorly linked with overall survival in lung adenocarcinomas. Furthermore, GINS4 promoted many characteristics of tumorigenesis including cell growth, clonal formation, migration and invasion, epithelial-mesenchymal transition, tumor sphere and tumor growth in vivo. Interestingly, our results demonstrated that LSH increases GINS4 expression through binding to 3'UTR region of GINS4 and stabilizing its mRNA levels. Finally, LSH overexpression rescues GINS4 knockdown-induced features., Conclusions: GINS4 facilitates lung cancer progression by promoting key characteristics of tumor potential, and LSH epigenetically interacts with and stabilizes GINS4 transcripts.

Background: We assessed the frequency of epigenetic lesions, including lymphoid-specific helicase (LSH), 5-hydroxymethylcytosine (5-hmC) and E2F1, and the possible correlations among molecular findings, phenotype, clinical features, and outcome., Methods: We investigated 181 paraffin-embedded B-cell lymphoma samples using immunohistochemistry and in situ hybridization., Results: The levels of Ki67, LSH, 5-hmC, and E2F1 were all increased in germinal center B-cell lymphomas when compared with those in normal lymph nodes, and LSH was highly expressed in diffuse large B-cell lymphomas (DLBCLs) and Burkitt lymphomas (BLs) that were positive for Epstein-Barr virus (EBV) infection, indicating that LSH is linked to EBV infection in DLBCL and BL. Interestingly, LSH was mainly localized in the germinal centers of lymph nodes whereas 5-hmC staining localized to areas surrounding the germinal centers., Conclusions: These findings indicate a critical role for LSH as a biomarker and therapeutic target in follicular germinal center B-cell lymphoma., Competing Interests: None

Long noncoding RNAs (lncRNA) have been associated with various types of cancer; however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression, respectively. P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466). The cytosolic P53RRA-G3BP1 interaction displaced p53 from a G3BP1 complex, resulting in greater p53 retention in the nucleus, which led to cell-cycle arrest, apoptosis, and ferroptosis. P53RRA promoted ferroptosis and apoptosis by affecting transcription of several metabolic genes. Low P53RRA expression significantly correlated with poor survival in patients with breast and lung cancers harboring wild-type p53. These data show that lncRNAs can directly interact with the functional domain of signaling proteins in the cytoplasm, thus regulating p53 modulators to suppress cancer progression. Significance: A cytosolic lncRNA functions as a tumor suppressor by activating the p53 pathway. Cancer Res; 78(13); 3484-96. ©2018 AACR ., (©2018 American Association for Cancer Research.)

DNA methylation is an important epigenetic modification as a hallmark in cancer. Conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by ten-eleven translocation (TET) family enzymes plays an important biological role in embryonic stem cells, development, aging and disease. Lymphoid specific helicase (LSH), a chromatin remodeling factor, is regarded as a reader of 5-hmC. Recent reports show that the level of 5-hmC is altered in various types of cancers. However, the change in 5-hmC levels in cancer and associated metastasis is not well defined. We report that the level of 5-hmC was decreased in metastatic tissues of nasopharyngeal carcinoma, breast cancer, and colon cancer relative to that in non-metastasis tumor tissues. Furthermore, our data show that TET2, but not TET3, interacted with LSH, whereas LSH increased TET2 expression through silencing miR-26b-5p and miR-29c-5p. Finally, LSH promoted genome stability by silencing satellite expression by affecting 5-hmC levels in pericentromeric satellite repeats, and LSH was resistant to cisplatin-induced DNA damage. Our data indicate that 5-hmC might serve as a metastasis marker for cancer and that the decreased expression of LSH is likely one of the mechanisms of genome instability underlying 5-hmC loss in cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists. This manuscript has been read and approved by all the authors, and not submitted or under consideration for publication elsewhere.

Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF-1α. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo . Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis, which can be exploited for the development of therapeutic strategies targeting ferroptosis for the treatment of cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The signaling pathway-based stratification in chromatin modification could predict clinical outcome more reliably than morphology-alone-based classification schemes in gliomas. Here we reported a role of the chromatin-remodeling factor lymphoid-specific helicase (LSH) in gliomas. Among astrocytomas of grade I to III and glioblastoma of grade IV, LSH were almost completely expressed in all cases, and strongly correlated with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Ectopic expression of LSH promoted tumor formation. Up-regulation of transcription factor E2F1 in astrocytomas and glioblastoma was associated with the progression of gliomas and correlated with LSH expression. Chromatin immunoprecipitation (ChIP) analysis showed transcription factor E2F1 were recruited to the promoter region of LSH, and depletion of E2F1 decreased LSH expression and cell growth. Moreover, glycogen synthase kinase-3β (GSK-3β), an intact complex of E2F1, were also highly expressed in astrocytomas and linked with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Inhibition of GSK3β increased the enrichment of E2F1 to the LSH promoter, in turn, increased LSH expression. Lipoprotein receptor-related protein 6 (LRP6), an upstream regulator of GSK3β signaling pathway, was highly expressed in gliomas. Knockdown of LRP6 decreased LSH expression through decrease of recruitment of E2F1 to the LSH promoter leading to inhibition of cell growth. Taken together, this study reveals evidence demonstrating a mechanism by which upregulated promoted gliomas. A mechanistic link between LSH expression and activation of the LPR6/ GSK3β/E2F1 axis in gliomas illustrates a novel role of LSH in malignant astrocytomas and glioblastoma., Competing Interests: The authors declare no conflict of interest. This manuscript has been read and approved by all the authors, and not submitted or under consider for publication elsewhere.

Chromatin modification is pivotal to the epithelial-mesenchymal transition (EMT), which confers potent metastatic potential to cancer cells. Here, we report a role for the chromatin remodeling factor lymphoid-specific helicase (LSH) in nasopharyngeal carcinoma (NPC), a prevalent cancer in China. LSH expression was increased in NPC, where it was controlled by the Epstein-Barr virus-encoded protein LMP1. In NPC cells in vitro and in vivo, LSH promoted cancer progression in part by regulating expression of fumarate hydratase (FH), a core component of the tricarboxylic acid cycle. LSH bound to the FH promoter, recruiting the epigenetic silencer factor G9a to repress FH transcription. Clinically, we found that the concentration of TCA intermediates in NPC patient sera was deregulated in the presence of LSH. RNAi-mediated silencing of FH mimicked LSH overexpression, establishing FH as downstream mediator of LSH effects. The TCA intermediates α-KG and citrate potentiated the malignant character of NPC cells, in part by altering IKKα-dependent EMT gene expression. In this manner, LSH furthered malignant progression of NPC by modifying cancer cell metabolism to support EMT. Cancer Res; 76(19); 5743-55. ©2016 AACR., (©2016 American Association for Cancer Research.)