Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression.

Breast cancer has become a serious threat to women's health. Cancer progression is mainly derived from resistance to apoptosis induced by procedures or therapies. Therefore, new drugs or models that can overcome apoptosis resistance should be identified. Ferroptosis is a recently identified mode of cell death characterized by excess reactive oxygen species-induced lipid peroxidation. Since ferroptosis is distinct from apoptosis, necrosis and autophagy, its induction successfully eliminates cancer cells that are resistant to other modes of cell death. Therefore, ferroptosis may become a new direction around which to design breast cancer treatment. Unfortunately, the complete appearance of ferroptosis in breast cancer has not yet been fully elucidated. Furthermore, whether ferroptosis inducers can be used in combination with traditional anti- breast cancer drugs is still unknown. Moreover, a summary of ferroptosis in breast cancer progression and therapy is currently not available. In this review, we discuss the roles of ferroptosis-associated modulators glutathione, glutathione peroxidase 4, iron, nuclear factor erythroid-2 related factor-2, superoxide dismutases, lipoxygenase and coenzyme Q in breast cancer. Furthermore, we provide evidence that traditional drugs against breast cancer induce ferroptosis, and that ferroptosis inducers eliminate breast cancer cells. Finally, we put forward prospect of using ferroptosis inducers in breast cancer therapy, and predict possible obstacles and corresponding solutions. This review will deepen our understanding of the relationship between ferroptosis and breast cancer, and provide new insights into breast cancer-related therapeutic strategies.

Targeting Histone Modifications in Breast Cancer: A Precise Weapon on the Way.

Histone modifications (HMs) contribute to maintaining genomic stability, transcription, DNA repair, and modulating chromatin in cancer cells. Furthermore, HMs are dynamic and reversible processes that involve interactions between numerous enzymes and molecular components. Aberrant HMs are strongly associated with tumorigenesis and progression of breast cancer (BC), although the specific mechanisms are not completely understood. Moreover, there is no comprehensive overview of abnormal HMs in BC, and BC therapies that target HMs are still in their infancy. Therefore, this review summarizes the existing evidence regarding HMs that are involved in BC and the potential mechanisms that are related to aberrant HMs. Moreover, this review examines the currently available agents and approved drugs that have been tested in pre-clinical and clinical studies to evaluate their effects on HMs. Finally, this review covers the barriers to the clinical application of therapies that target HMs, and possible strategies that could help overcome these barriers and accelerate the use of these therapies to cure patients.

Long Noncoding RNAs Control the Modulation of Immune Checkpoint Molecules in Cancer.

Long noncoding RNAs (lncRNA) that are associated with immune checkpoints have not been identified, and the mechanism by which such lncRNAs might regulate the expression of immune checkpoints is unknown in human cancer. Immune checkpoint-associated lncRNAs (ICP-lncRNA) were identified and validated via a comprehensive bioinformatic analysis of The Cancer Genome Atlas data. These ICP-lncRNAs were involved in key immune response and immune cell receptor signaling pathways. The expression of ICP-lncRNAs was upregulated and correlated with a poor prognosis in patients with cancer. HLA complex P5 (HCP5) and myocardial infarction associated transcript (MIAT) promoted tumor growth and upregulated the expression of PD-L1/CD274 via a competing endogenous RNA mechanism of sponging miR-150-5p. The combination of MIAT knockdown and PD-L1 antibody administration showed a synergistic inhibitory effect on tumor growth. Finally, the expression of both HCP5 and MIAT was confirmed to be transcriptionally suppressed by CCCTC-binding factor (CTCF), and lipopolysaccharide induced CTCF eviction from the HCP5 and MIAT promoters, attenuating the transcriptionally suppressive activity of CTCF. This study enlarges the functional landscape of known lncRNAs in human cancer and indicates novel insights into their roles in the field of tumor immunity and immunotherapy. These findings may aid in the comprehensive management of human cancer with immunotherapy.

Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin.

Glutathione peroxidase 4 (GPX4) has been confirmed to inhibit ferroptosis in cancer cells, however, whether GPX4 serves as an oncogene is not clear. In this study, the expression of GPX4 and its influence to survival of patients with cancer were analyzed via public databases. Furthermore, the epigenetic regulation of GPX4 and the relation between GPX4 and chemoresistance of different anticancer drugs was also detected. Most importantly, cytological assays were performed to investigate the function of GPX4 in cancer cells. The results showed that GPX4 was higher expressed in cancer tissues than normal and was negatively associated with prognosis of patients. Furthermore, at upstream of GPX4 there was low DNA methylation sites and enhanced level of H3K4me3 and H3K27ac, indicating that high level of GPX4 in cancer may resulted from epigenetic regulation. Moreover, GPX4 was positively related to chemoresistance of anticancer drugs L-685458, lapatinib, palbociclib, and topotecan. In addition, GPX4 may potentially be involved in translation of protein, mitochondrial respiratory chain complex I assembly, electron transport oxidative phosphorylation, nonalcoholic fatty liver disease, and metabolic pathways. Finally, we detected that GPX4 inhibited ferroptosis in cancer cells, the inhibition of GPX4 via RSL3 could enhance the anticancer effect of cisplatin in vitro and in vivo. In conclusion, GPX4 acts as an oncogene and inhibits ferroptosis in cancer cells, the anticancer effect of cisplatin can be enhanced by GPX4 inhibition.

The transcriptional landscape of lncRNAs reveals the oncogenic function of LINC00511 in ER-negative breast cancer.

Advances in the molecular characteristics of cancers have facilitated the classification system from morphology to molecular characteristic-based subtypes. Cancer profiling has expanded in its focus from protein-coding genes to noncoding RNAs, with advances in the depth and quality of transcriptome sequencing. Here, we examined the profiles of long noncoding RNAs (lncRNAs) according to breast cancer subtype categories in The Cancer Genome Atlas (TCGA) database to identify a cohort of breast cancer- and oestrogen receptor (ER)-negative-associated lncRNAs. According to the prioritization of variation in ER-negative-associated lncRNAs, we identified and investigated the role of LINC00511 in breast cancer. We determined that high LINC00511 expression was an unfavourable prognostic factor for patients with breast cancer. Furthermore, LINC00511 promoted tumour growth by accelerating the G1/S transition and inhibiting apoptosis. At the transcriptional level, ER deficiency directly affected the expression of LINC00511 activated by transcription factor AP-2 (TFAP-2) in breast cancer cells. Moreover, mechanistic investigations demonstrated that ER-negative-associated LINC00511 interacted with enhancer of zeste homologue 2 (EZH2, the catalytic subunit of polycomb repressive complex 2, PRC2) and recruited PRC2 to mediate histone methylation, contributing to the repression of CDKN1B in the nucleus. This process resulted in altered ER-negative breast cancer cell biology. By highlighting the oncogenic function of LINC00511, we revealed the role of lncRNAs in regulating the network of cell cycle control in ER-negative breast cancer and suggested the exploitation of LINC00511 as an anticancer therapy in the future.

Ferritinophagy is required for the induction of ferroptosis by the bromodomain protein BRD4 inhibitor (+)-JQ1 in cancer cells.

(+)-JQ1 is an inhibitor of the tumor-driver bromodomain protein BRD4 and produces satisfactory effects because it efficiently increases apoptosis. Ferroptosis is an oxidative cell death program differing from apoptosis. Ferroptosis is characterized by high levels of iron and reactive oxygen species and has been confirmed to suppress tumor growth. In this study, BRD4 expression in cancer and its influence on the prognosis of cancer patients were analyzed using data from public databases. In addition, the effect of the BRD4 inhibitor (+)-JQ1 on ferroptosis was investigated via a series of in vitro assays. A nude mouse model was used to evaluate the function of (+)-JQ1 in ferroptosis in vivo. The potential mechanisms by which (+)-JQ1 regulates ferroptosis were explored. The results showed that BRD4 expression levels were higher in cancer tissues than in normal tissues and were related to poor prognosis in cancer patients. Furthermore, ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition. Moreover, the anticancer effect of (+)-JQ1 was enhanced by ferroptosis inducers. Further studies confirmed that (+)-JQ1 induced ferroptosis via ferritinophagy, which featured autophagy enhancement by (+)-JQ1 and increased iron levels. Subsequently, the reactive oxygen species levels were increased by iron via the Fenton reaction, leading to ferroptosis. In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 may regulate ferroptosis by controlling the expression of ferroptosis-associated genes regulated by BRD4. Finally, (+)-JQ1 regulated ferritinophagy and the expression of ferroptosis-associated genes via epigenetic inhibition of BRD4 by suppressing the expression of the histone methyltransferase G9a or enhancing the expression of the histone deacetylase SIRT1. In summary, the BRD4 inhibitor (+)-JQ1 induces ferroptosis via ferritinophagy or the regulation of ferroptosis-associated genes through epigenetic repression of BRD4.

Ai-lncRNA EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions in human cancer.

BACKGROUND: The biology function of antisense intronic long noncoding RNA (Ai-lncRNA) is still unknown. Meanwhile, cancer patients with paclitaxel resistance have limited therapeutic options in the clinic. However, the potential involvement of Ai-lncRNA in paclitaxel sensitivity remains unclear in human cancer. METHODS: Whole transcriptome sequencing of 33 breast specimens was performed to identify Ai-lncRNA EGOT. Next, the role of EGOT in regulation of paclitaxel sensitivity was investigated. Moreover, the mechanism of EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions was investigated in detail. Furthermore, upstream transcriptional regulation of EGOT expression was also investigated by co-immunoprecipitation and chromatin immunoprecipitation. Finally, clinical breast specimens in our cohort, TCGA and ICGC were applied to validate the role of EGOT in enhancing of paclitaxel sensitivity. RESULTS: EGOT enhances autophagosome accumulation via the up-regulation of ITPR1 expression, thereby sensitizing cells to paclitaxel toxicity. Mechanistically, on one hand, EGOT upregulates ITPR1 levels via formation of a pre-ITPR1/EGOT dsRNA that induces pre-ITPR1 accumulation to increase ITPR1 protein expression in cis. On the other hand, EGOT recruits hnRNPH1 to enhance the alternative splicing of pre-ITPR1 in trans via two binding motifs in EGOT segment 2 (324-645 nucleotides) in exon 1. Moreover, EGOT is transcriptionally regulated by stress conditions. Finally, EGOT expression enhances paclitaxel sensitivity via assessment of cancer specimens. CONCLUSIONS: These findings broaden comprehensive understanding of the biology function of Ai-lncRNAs. Proper regulation of EGOT may be a novel synergistic strategy for enhancing paclitaxel sensitivity in cancer therapy.

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses.

Autophagy is central to the maintenance of intracellular homeostasis across species. Accordingly, autophagy disorders are linked to a variety of diseases from the embryonic stage until death, and the role of autophagy as a therapeutic target has been widely recognized. However, autophagy-associated therapy for human diseases is still in its infancy and is supported by limited evidence. In this review, we summarize the landscape of autophagy-associated diseases and current autophagy modulators. Furthermore, we investigate the existing autophagy-associated clinical trials, analyze the obstacles that limit their progress, offer tactics that may allow barriers to be overcome along the way and then discuss the therapeutic potential of autophagy modulators in clinical applications.

Upregulation of DLEU1 expression by epigenetic modification promotes tumorigenesis in human cancer.

The function of DLEU1 in human cancer is largely unknown. The Cancer Genome Atlas data were applied to identify the landscape of differential genes between tumor tissues and normal tissues, which was further validated by our cohort data and pan-cancer data including 33 cancer types with 11,060 patients. Next, DLEU1 was selected to validate the novel finding and result showed that it promoted tumorigenesis in vitro and in vivo. Mechanistically, DLEU1 promotes SRP4 expression via increasing H3K27ac enrichment to SRP4 locus epigenetically. Moreover, epigenetic modification leads to upregulation of DLEU1 expression via decreased DNA methylation and increased H3K27ac and H3K4me3 histone modification in its locus. Finally, high expression of DLEU1 correlates with worse prognosis not only in specific cancer type patients but also in patients in the pan-cancer cohort. In summary, the work broadens the function landscape of known long noncoding RNAs in human cancer and provides novel insights into their roles in tumorigenesis.

Downregulation of long noncoding RNA MALAT1 induces epithelial-to-mesenchymal transition via the PI3K-AKT pathway in breast cancer.

The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) regulates cell motility via the transcriptional or post-transcriptional control of motility-related genes. Whether MALAT1 plays a critical role in cancer progression in breast cancer remains unclear. In this study, we found that MALAT1 was downregulated in breast tumor cell lines and cancer tissue, and showed that knockdown of MALAT1 in breast cancer cell lines induced an epithelial-to-mesenchymal transition (EMT) program via phosphatidylinositide-3 kinase-AKT pathways. Furthermore, lower expression of MALAT1 in breast cancer patients was associated with shorter relapse-free survival. Thus, our results indicate for the first time that MALAT1 is a novel regulator of EMT in breast cancer and may be a potential therapeutic target for breast cancer metastasis.

Downregulation of the long noncoding RNA EGOT correlates with malignant status and poor prognosis in breast cancer.

Eosinophil granule ontogeny transcript (EGOT) is a long noncoding RNA involved in the regulation of eosinophil granule protein transcript expression. However, little is known about the role of EGOT in malignant disease. This study aimed to assess the potential role of EGOT in the pathogenesis of breast cancer. Quantitative real-time polymerase chain reaction was performed to detect the expression levels of EGOT in 250 breast cancerous tissues and 50 adjacent noncancerous tissues. The correlation of EGOT expression with clinicopathological features and prognosis was also analyzed. EGOT expression was lower in breast cancer compared with the adjacent noncancerous tissues (P < 0.001), and low levels of EGOT expression were significantly correlated with larger tumor size (P = 0.022), more lymph node metastasis (P = 0.020), and higher Ki-67 expression (P = 0.017). Moreover, patients with low levels of EGOT expression showed significantly worse prognosis for overall survival (P = 0.040), and this result was further validated in a larger cohort from a public database. Multivariate analysis suggested that low levels of EGOT were a poor independent prognostic predictor for breast cancer patients (HR = 1.857, 95 % CI = 1.032-3.340, P = 0.039). In conclusion, EGOT may play an important role in breast cancer progression and prognosis and may serve as a new potential prognostic target in breast cancer patients.