The roles and mechanisms of SREBP1 in cancer development and drug response.

Cancer occurrence and development are closely related to increased lipid production and glucose consumption. Lipids are the basic component of the cell membrane and play a significant role in cancer cell processes such as cell-to-cell recognition, signal transduction, and energy supply, which are vital for cancer cell rapid proliferation, invasion, and metastasis. Sterol regulatory element-binding transcription factor 1 (SREBP1) is a key transcription factor regulating the expression of genes related to cholesterol biosynthesis, lipid homeostasis, and fatty acid synthesis. In addition, SREBP1 and its upstream or downstream target genes are implicated in various metabolic diseases, particularly cancer. However, no review of SREBP1 in cancer biology has yet been published. Herein, we summarized the roles and mechanisms of SREBP1 biological processes in cancer cells, including SREBP1 modification, lipid metabolism and reprogramming, glucose and mitochondrial metabolism, immunity, and tumor microenvironment, epithelial-mesenchymal transition, cell cycle, apoptosis, and ferroptosis. Additionally, we discussed the potential role of SREBP1 in cancer prognosis, drug response such as drug sensitivity to chemotherapy and radiotherapy, and the potential drugs targeting SREBP1 and its corresponding pathway, elucidating the potential clinical application based on SREBP1 and its corresponding signal pathway.

E3 ubiquitin ligase RNF148 functions as an oncogene in colorectal cancer by ubiquitination-mediated degradation of CHAC2.

We previously reported that RNF148 was involved in the ubiquitination-mediated degradation of CHAC2. However, its molecular mechanism was not determined. In this study, we investigated the role and mechanism of RNF148 in the progression of colorectal cancer (CRC), especially in the process of ubiquitination-mediated degradation of CHAC2. Our results revealed that RNF148 was upregulated in most CRC tissues, and its expression significantly correlated with the 3-year overall survival rate and most clinicopathological parameters of CRC patients. Furthermore, RNF148 served as an independent prognostic biomarker of CRC and promoted CRC cell proliferation and migration while inhibiting cell apoptosis and sensitivity to 5-FU. Mechanistically, RNF148 used its protease-associated domain to bind to the CHAC domain of CHAC2 and target it for degradation. In addition, we identified two phosphorylation and three ubiquitination residues of CHAC2 and identified Y118 and K102 as the critical phosphorylation and ubiquitination residues, respectively. We also identified CHAC2's and RNF148's interacting proteins and discovered their potential interaction network. In conclusion, our current study unveiled the role of RNF148 in CRC and the mechanism of RNF148 in the ubiquitination-mediated degradation of CHAC2, which shed light on providing potential prognostic biomarkers and molecular targets for CRC patients.

The Biological Functions and Regulatory Mechanisms of Fatty Acid Binding Protein 5 in Various Diseases.

In recent years, fatty acid binding protein 5 (FABP5), also known as fatty acid transporter, has been widely researched with the help of modern genetic technology. Emerging evidence suggests its critical role in regulating lipid transport, homeostasis, and metabolism. Its involvement in the pathogenesis of various diseases such as metabolic syndrome, skin diseases, cancer, and neurological diseases is the key to understanding the true nature of the protein. This makes FABP5 be a promising component for numerous clinical applications. This review has summarized the most recent advances in the research of FABP5 in modulating cellular processes, providing an in-depth analysis of the protein's biological properties, biological functions, and mechanisms involved in various diseases. In addition, we have discussed the possibility of using FABP5 as a new diagnostic biomarker and therapeutic target for human diseases, shedding light on challenges facing future research.

Biological functions of m6A methyltransferases.

M6A methyltransferases, acting as a writer in N6-methyladenosine, have attracted wide attention due to their dynamic regulation of life processes. In this review, we first briefly introduce the individual components of m6A methyltransferases and explain their close connections to each other. Then, we concentrate on the extensive biological functions of m6A methyltransferases, which include cell growth, nerve development, osteogenic differentiation, metabolism, cardiovascular system homeostasis, infection and immunity, and tumour progression. We summarize the currently unresolved problems in this research field and propose expectations for m6A methyltransferases as novel targets for preventive and curative strategies for disease treatment in the future.

The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by ß-elemene.

N6-methyladenosine (m6A) modification can alter gene expression by regulating RNA splicing, stability, translocation, and translation. Emerging evidence shows that m6A modification plays an important role in cancer development and progression, including cell proliferation, migration and invasion, cell apoptosis, autophagy, and drug resistance. Until now, the role of m6A modification mediated autophagy in cancer drug resistance is still unclear. In this study, we found that m6A methyltransferase METTL3-mediated autophagy played an important role in reversing gefitinib resistance by ß-elemene in non-small cell lung cancer (NSCLC) cells. Mechanistically, in vitro and in vivo studies indicated that ß-elemene could reverse gefitinib resistance in NSCLC cells by inhibiting cell autophagy process in a manner of chloroquine. ß-elemene inhibited the autophagy flux by preventing autophagic lysosome acidification, resulting in increasing expression of SQSTM1 and LC3B-II. Moreover, both ß-elemene and gefitinib decreased the level of m6A methylation of gefitinib resistance cells. METTL3 was higher expressed in lung adenocarcinoma tissues than that of paired normal tissues, and was involved in the gefitinib resistance of NSCLC cells. Furthermore, METTL3 positively regulated autophagy by increasing the critical genes of autophagy pathway such as ATG5 and ATG7. In conclusion, our study unveiled the mechanism of METTL3-mediated autophagy in reversing gefitinib resistance of NSCLC cells by ß-elemene, which shed light on providing potential molecular-therapy target and clinical-treatment method in NSCLC patients with gefitinib resistance.

METTL3 plays multiple functions in biological processes.

N6-methyladenosine (m6A) is the most common internal modification of mRNAs in higher eukaryotic. This process is performed by methyltransferase. Methyltransferase-like 3 (METTL3) is the best known m6A methyltransferase that functions in the reversible epi-transcriptome modulation of m6A modification. Besides acting as a m6A methyltransferase, METTL3 also regulates mRNA translation and other biological processes. In recent years, studies have identified numerous roles and molecular mechanisms associated with METTL3 in multiple biological processes. However, these findings have not been summarized. In this review, we have systematically summarized the most recent important roles of METTL3 in various biological processes, including cell cycle progression, cell proliferation, cell apoptosis, cell migration and invasion, cell differentiation and inflammatory response. In addition, we discuss the prospect of using a METTL3 as a new diagnostic biomarker and therapeutic target for human cancers.

The roles and mechanisms of YTH domain-containing proteins in cancer development and progression.

Evolutionarily conserved YT521-B homology (YTH) domain-containing proteins, including YTHDF1-3 and YTHDC1-2, are known to confer m6A-dependent RNA-binding activity. The YTH domain-containing proteins participate in numerous RNA processes, such as mRNA splicing, nuclear export, translation and decay in post-transcriptional regulation. Most recently, it has been found that YTH domain-containing proteins play important roles in post-transcriptional modification process hence modulate the expression of genes involved in cancer and other processes including cell cycle progression, cell proliferation, migration and invasion, inflammatory, immunity and autophagy. In this review, we summarize the roles and molecular mechanisms of YTH domain-containing proteins in cancer development and progression. In addition, we discuss the prospect of using YTH domain-containing proteins as a new diagnostic biomarkers and therapeutic targets for cancers.

Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis.

Ferroptosis, a novel form of programmed cell death, is characterized by iron-dependent lipid peroxidation and has been shown to be involved in multiple diseases, including cancer. Stimulating ferroptosis in cancer cells may be a potential strategy for cancer therapy. Therefore, ferroptosis-inducing drugs are attracting more attention for cancer treatment. Here, we showed that erianin, a natural product isolated from Dendrobium chrysotoxum Lindl, exerted its anticancer activity by inducing cell death and inhibiting cell migration in lung cancer cells. Subsequently, we demonstrated for the first time that erianin induced ferroptotic cell death in lung cancer cells, which was accompanied by ROS accumulation, lipid peroxidation, and GSH depletion. The ferroptosis inhibitors Fer-1 and Lip-1 but not Z-VAD-FMK, CQ, or necrostatin-1 rescued erianin-induced cell death, indicating that ferroptosis contributed to erianin-induced cell death. Furthermore, we demonstrated that Ca2+/CaM signaling was a critical mediator of erianin-induced ferroptosis and that blockade of this signaling significantly rescued cell death induced by erianin treatment by suppressing ferroptosis. Taken together, our data suggest that the natural product erianin exerts its anticancer effects by inducing Ca2+/CaM-dependent ferroptosis and inhibiting cell migration, and erianin will hopefully serve as a prospective compound for lung cancer treatment.

ß-Elemene Reverses the Resistance of p53-Deficient Colorectal Cancer Cells to 5-Fluorouracil by Inducing Pro-death Autophagy and Cyclin D3-Dependent Cycle Arrest.

OBJECTIVE: Colorectal cancer is a malignant tumor of the digestive system with high morbidity and mortality. 5-fluorouracil remains a widely used chemotherapeutic drug in the treatment of advanced colorectal cancer, but chemotherapy drugs are prone to develop drug resistance, p53 deletion or mutation is an important reason for the resistance of colorectal cancer cells to 5-fluorouracil. ß-elemene has been proved to have the potential of reverse chemotherapy drug resistance, but the mechanism is unknown. This study aimed to investigate the effect of ß-elemene to 5-fluorouracil in drug-resistant p53-deficient colorectal cancer cells HCT116p53-/-, and determine the possible molecular mechanism of ß-elemene to reverse 5-fluorouracil resistance. METHODS: The effect of ß-elemene on HCT116p53-/- cell activity was detected by Cell counting Kit-8. Cell proliferation was detected by monoclonal plate. The apoptosis was detected by flow cytometry and western blot. The autophagy was detected by western blot, immunofluorescence and transmission electron microscope. Determine the role of Cyclin-related protein Cyclin D3 in ß-elemene reversing the resistance of HCT116p53-/- to 5-fluorouracil was detected by overexpression of Cyclin D3. The effect of ß-elemene on the tumorigenic ability of p53-deficient colorectal cancer cells was detected establishing HCT116p53-/- all line xenograft model. RESULTS: For p53 wildtype colorectal cancer cells, ß-elemene could augment the sensitivity of 5-fluorouracil, for p53-deficient colorectal cancer cells, ß-elemene significantly inhibited cell proliferation in a concentration-dependent manner, and reversed the resistance of HCT116p53-/- to 5-fluorouracil by inducing pro-death autophagy and Cyclin D3-dependent cycle arrest. CONCLUSION: ß-elemene enhances the sensitivity of p53 wild-type cells to 5-fluorouracil, ß-elemene can reverse the resistance of HCT116p53-/- to 5-fluorouracil by inducing pro-death autophagy and Cyclin D3-dependent cycle arrest in p53-deficient colorectal cancer, which will provide a new method for the treatment of p53 deletion colorectal cancer patients.

The emerging molecular mechanism of m6A modulators in tumorigenesis and cancer progression.

N6-methyladenosine (m6A) is the most abundant RNA modification; m6A modifications are installed by methyltransferases, removed by demethylases and recognized by reader proteins. M6A plays crucial roles in a variety of biological processes by regulating target RNA translation, splicing, nuclear export, and decay. Since the establishment of methylated RNA immunoprecipitation-sequencing methodology, over three hundred articles about m6A modulators, including "writers", "erasers" and "readers", have been reported in the last four years. In addition, an increasing number of molecular mechanisms underlying m6A RNA methylation in human cancers have been comprehensively clarified. The recently emerged molecular mechanisms of m6A modulators in cancer cell proliferation, cell cycle progression, migration and invasion, apoptosis, and autophagy remain to be summarized. Hence, this review specifically summarizes these recent advances in the understanding of m6A molecular mechanisms in tumorigenesis and cancer progression. In addition, we discuss the prospect of using an m6A methylation modulator as a new diagnostic biomarker and therapeutic target for human cancers.

Combinative treatment of ß-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation.

Background and Purpose: RAS mutations limit the effectiveness of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in combination with chemotherapy for metastatic colorectal cancer (mCRC) patients. Therefore, new cell death forms have focused on identifying indirect targets to inhibit Ras-induced oncogenesis. Recently, emerging evidence has shown the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Methods: KRAS mutant CRC cell HCT116 and Lovo were treated with cetuximab and ß-elemene, a bioactive compound isolated from Chinese herb Curcumae Rhizoma. Ferroptosis and epithelial-mesenchymal transformation (EMT) were detected in vitro and in vivo. Orthotopic CRC animal model were established and the tumor growth was monitored by IVIS bioluminescence imaging. Tumor tissues were collected to determine ferroptosis effect and the expression of EMT markers after the treatment. Results: CCK-8 assay showed that synergetic effect was obtained when 125 µg/ml ß-elemene was combined with 25 µg/ml cetuximab in KRAS mutant CRC cells. AV/PI staining suggested a non-apoptotic mode of cell death after the treatment with ß-elemene and cetuximab. In vitro, ß-elemene in combination with cetuximab was shown to induce iron-dependent reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, upregulation of HO-1 and transferrin, and downregulation of negative regulatory proteins for ferroptosis (GPX4, SLC7A11, FTH1, glutaminase, and SLC40A1) in KRAS mutant CRC cells. Meanwhile, combinative treatment of ß-elemene and cetuximab inhibited cell migration and decreased the expression of mesenchymal markers (Vimentin, N-cadherin, Slug, Snail and MMP-9), but promoted the expression of epithelial marker E-cadherin. Moreover, ferroptosis inhibitors but not other cell death suppressors abrogated the effect of ß-elemene in combination with cetuximab on KRAS mutant CRC cells. In vivo, co-treatment with ß-elemene and cetuximab inhibited KRAS mutant tumor growth and lymph nodes metastases. Conclusions: Our data for the first time suggest that the natural product ß-elemene is a new ferroptosis inducer and combinative treatment of ß-elemene and cetuximab is sensitive to KRAS mutant CRC cells by inducing ferroptosis and inhibiting EMT, which will hopefully provide a prospective strategy for CRC patients with RAS mutations.

PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death.

5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.