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Biochemical Society Transactions Jun 2023RAS proteins are small GTPases that transduce signals from membrane receptors to signaling pathways that regulate growth and differentiation. Four RAS proteins are... (Review)
Review
RAS proteins are small GTPases that transduce signals from membrane receptors to signaling pathways that regulate growth and differentiation. Four RAS proteins are encoded by three genes - HRAS, KRAS, NRAS. Among them, KRAS is mutated in human cancer more frequently than any other oncogene. The KRAS pre-mRNA is alternatively spliced to generate two transcripts, KRAS4A and KRAS4B, that encode distinct proto-oncoproteins that differ almost exclusively in their C-terminal hypervariable regions (HVRs) that controls subcellular trafficking and membrane association. The KRAS4A isoform arose 475 million years ago in jawed vertebrates and has persisted in all vertebrates ever since, strongly suggesting non-overlapping functions of the splice variants. Because KRAS4B is expressed at higher levels in most tissues, it has been considered the principal KRAS isoform. However, emerging evidence for KRAS4A expression in tumors and splice variant-specific interactions and functions have sparked interest in this gene product. Among these findings, the KRAS4A-specific regulation of hexokinase I is a stark example. The aim of this mini-review is to provide an overview of the origin and differential functions of the two splice variants of KRAS.
Topics: Animals; Humans; Proto-Oncogene Proteins p21(ras); Neoplasms; Protein Isoforms; Signal Transduction; ras Proteins; Mutation
PubMed: 37222266
DOI: 10.1042/BST20221347 -
Cell Reports Dec 2023KRAS mutations are frequently detected in non-small cell lung cancers (NSCLCs). Although covalent KRAS inhibitors have been developed to treat KRAS-mutant cancers,...
KRAS mutations are frequently detected in non-small cell lung cancers (NSCLCs). Although covalent KRAS inhibitors have been developed to treat KRAS-mutant cancers, effective treatments are still lacking for other KRAS-mutant NSCLCs. Thus, identifying a KRAS effector that confers poor prognosis would provide an alternative strategy for the treatment of KRAS-driven cancers. Here, we show that KRAS drives expression of deubiquitinase USP13 through Ras-responsive element-binding protein 1 (RREB1). Elevated USP13 promotes KRAS-mutant NSCLC metastasis, which is associated with poor prognosis in NSCLC patients. Mechanistically, USP13 interacts with and removes the K63-linked polyubiquitination of β-catenin at lysine 508, which enhances the binding between β-catenin and transcription factor TCF4. Importantly, we identify 2-methoxyestradiol as an effective inhibitor for USP13 from a natural compound library, and it could potently suppress the metastasis of KRAS-mutant NSCLC cells in vitro and in vivo. These findings identify USP13 as a therapeutic target for metastatic NSCLC with KRAS mutations.
Topics: Humans; beta Catenin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Lung Neoplasms; Mutation; Proto-Oncogene Proteins p21(ras); Ubiquitin-Specific Proteases
PubMed: 38043062
DOI: 10.1016/j.celrep.2023.113511 -
Molecular Cancer Oct 2023Lysine crotonylation (Kcr) is up-regulation in colorectal cancer (CRC) tissues, while its specific contribution remains uncertain. This study aimed to elucidate the role...
BACKGROUND
Lysine crotonylation (Kcr) is up-regulation in colorectal cancer (CRC) tissues, while its specific contribution remains uncertain. This study aimed to elucidate the role and mechanism of crotonylation on Lys27 of histone H3 (H3K27cr) in facilitating CRC metastasis.
METHODS
Immunohistochemistry was employed to investigate the correlation between H3K27cr and CRC metastasis. Both in vitro and in vivo assays employing loss function or gain function approaches were conducted to elucidate the role of LINC00922 in promoting CRC metastasis. ScRNA-seq analysis and immunoprecipitation analyses were employed to explore the underlying mechanism by which LINC00922 facilitates CRC metastasis through H3K27cr.
RESULTS
Clinically, H3K27cr was upregulated in metastatic CRC tissues and positively correlated with advanced clinical stages. Functionally, knockdown of LINC00922 inhibited migration of CRC cells both in vitro and in vivo. Furthermore, the supplementation of NaCr restored the migration and invasion levels of LINC00922 stable knockdown cells by restoring the H3K27cr level. Mechanistically, LINC00922 promoted invasion and migration through H3K27cr mediated cell adhesion molecules (CAMs) in epithelial cells. Notably, LINC00922 interacted with the protein sirtuin 3 (SIRT3) and obstructed its binding to the promoter region of ETS1, leading to an elevation in the level of H3K27cr in this promoter region and the subsequent activation of ETS1 transcription.
CONCLUSIONS
Our findings uncovered a novel regulatory function of H3K27cr, regulated by LINC00922, in facilitating CRC metastasis. This discovery contributed to a deeper comprehension of the involvement of histone crotonylation in the metastatic process of CRC.
Topics: Humans; Up-Regulation; Sirtuin 3; Transcriptional Activation; Histones; Colorectal Neoplasms; Promoter Regions, Genetic; Cell Line, Tumor; Cell Movement; Gene Expression Regulation, Neoplastic; Cell Proliferation; Neoplasm Metastasis; Proto-Oncogene Protein c-ets-1
PubMed: 37789393
DOI: 10.1186/s12943-023-01859-y -
Trends in Cancer May 2024Gene fusions and rearrangements play a crucial role in tumor biology. They are rare events typically detected in KRAS wild-type (WT) pancreatic tumors. Their... (Review)
Review
Gene fusions and rearrangements play a crucial role in tumor biology. They are rare events typically detected in KRAS wild-type (WT) pancreatic tumors. Their identification can inform clinical management by enabling precision oncology, as fusions involving BRAF, FGFR2, RET, NTRK, NRG1, and ALK represent actionable targets in KRAS-WT cancers, and serve diagnostic purposes since fusions involving PRKACA/B represent the diagnostic hallmark of intraductal oncocytic papillary neoplasms (IOPNs). Although they are rare, the therapeutic and diagnostic importance of these genomic events should not be underestimated, highlighting the need for quality-ensured molecular diagnostics in the management of cancer. Herein we review the existing literature on the role of fusion genes in pancreatic tumors and their clinical potential as effective biomarkers and therapeutic targets.
Topics: Humans; Pancreatic Neoplasms; Oncogene Proteins, Fusion; Biomarkers, Tumor; Receptor, trkA; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins B-raf; Receptor, Fibroblast Growth Factor, Type 2; Neuregulin-1; Anaplastic Lymphoma Kinase; Gene Fusion
PubMed: 38378317
DOI: 10.1016/j.trecan.2024.01.009 -
Drug Resistance Updates : Reviews and... Jul 2023MYC is a proto-oncogene that encodes a powerful regulator of transcription and cellular programs essential for normal development, as well as the growth and survival of... (Review)
Review
MYC is a proto-oncogene that encodes a powerful regulator of transcription and cellular programs essential for normal development, as well as the growth and survival of various types of cancer cells. MYC rearrangement and amplification is a common cause of hematologic malignancies. In epithelial cancers such as colorectal cancer, genetic alterations in MYC are rare. Activation of Wnt, ERK/MAPK, and PI3K/mTOR pathways dramatically increases Myc levels through enhanced transcription, translation, and protein stability. Elevated Myc promotes stress adaptation, metabolic reprogramming, and immune evasion to drive cancer development and therapeutic resistance through broad changes in transcriptional and translational landscapes. Despite intense interest and effort, Myc remains a difficult drug target. Deregulation of Myc and its targets has profound effects that vary depending on the type of cancer and the context. Here, we summarize recent advances in the mechanistic understanding of Myc-driven oncogenesis centered around mRNA translation and proteostress. Promising strategies and agents under development to target Myc are also discussed with a focus on colorectal cancer.
Topics: Humans; Proto-Oncogene Proteins c-myc; Cell Transformation, Neoplastic; Colorectal Neoplasms
PubMed: 37119690
DOI: 10.1016/j.drup.2023.100963 -
Seminars in Diagnostic Pathology Jan 2024Hereditary papillary renal cell carcinoma (HPRCC) is an autosomal dominant syndrome characterized by the occurrence of bilateral and multifocal, classic type papillary... (Review)
Review
Hereditary papillary renal cell carcinoma (HPRCC) is an autosomal dominant syndrome characterized by the occurrence of bilateral and multifocal, classic type papillary renal cell carcinomas. In the recent decades, extensive molecular studies have narrowed the molecular underpinnings of this syndrome to missense mutations in tyrosine kinase domain of MET proto-oncogene. Although MET mutations are specific to HPRCC, it has been found in sporadic papillary renal cell carcinomas and as recently reported, in biphasic squamoid alveolar variant of papillary renal cell carcinoma. Dual MET/VEGFR2 kinase inhibitor and tyrosine kinase inhibitors have shown promising results in systemic therapy for HPRCC.
Topics: Humans; Carcinoma, Renal Cell; Proto-Oncogene Proteins c-met; Germ-Line Mutation; Proto-Oncogene Mas; Kidney Neoplasms; Neoplastic Syndromes, Hereditary
PubMed: 38135585
DOI: 10.1053/j.semdp.2023.12.002 -
Blood May 2024Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins,...
Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.
Topics: Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Drug Resistance, Neoplasm; Animals; Hematologic Neoplasms; Mice; Antineoplastic Agents; Xenograft Model Antitumor Assays; Cell Line, Tumor; Mutation; Apoptosis
PubMed: 38211332
DOI: 10.1182/blood.2023019706 -
Chinese Medical Journal Dec 2023Melanoma accounts for a small proportion of skin cancers diagnosed each year, but it has a high degree of malignancy and rapid progression, resulting in a short survival... (Review)
Review
Melanoma accounts for a small proportion of skin cancers diagnosed each year, but it has a high degree of malignancy and rapid progression, resulting in a short survival period for patients. The incidence of melanoma continues to rise, and now melanoma accounts for 1.7% of cancer diagnoses worldwide and is the fifth most common cancer in the United States. With the development of high-throughput sequencing technologies, the understanding of the pathophysiology of melanoma had also been improved. The most common activating mutations in melanoma cells are BRAF , NRAS , and KIT mutations, which disrupt cell signaling pathways related to tumor proliferation. The progress has led to the emergence of molecularly targeted drugs, which extends the survival of patients with advanced melanoma. A large number of clinical trials have been conducted to confirm that targeted therapy for patients with advanced melanoma can improve progression-free survival and overall survival, and for stage III patients after radical tumor resection targeted therapy can reduce the recurrence of melanoma. Patients who were originally stage III or IV inoperable have the opportunity to achieve tumor radical resection after targeted therapy. This article reviewed the clinical trial data and summarized the clinical benefits and limitations of these therapies.
Topics: Humans; United States; Melanoma; Skin Neoplasms; Mutation; Proto-Oncogene Proteins B-raf
PubMed: 37144745
DOI: 10.1097/CM9.0000000000002692 -
The Journal of Clinical Investigation Aug 2023Despite the success of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to cotarget...
Despite the success of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to cotarget RAS and mTOR pathways; however, toxicity due to broad mTOR inhibition has limited its utility. Therefore, we sought to develop a more refined means of targeting cap-dependent translation and identifying the most therapeutically important eukaryotic initiation factor 4F complex-translated (eIF4F-translated) targets. Here, we show that an eIF4A inhibitor, which targets a component of eIF4F, dramatically enhances the effects of KRAS G12C inhibitors in NSCLCs and together these agents induce potent tumor regression in vivo. By screening a broad panel of eIF4F targets, we show that this cooperativity is driven by effects on BCL-2 family proteins. Moreover, because multiple BCL-2 family members are concomitantly suppressed, these agents are broadly efficacious in NSCLCs, irrespective of their dependency on MCL1, BCL-xL, or BCL-2, which is known to be heterogeneous. Finally, we show that MYC overexpression confers sensitivity to this combination because it creates a dependency on eIF4A for BCL-2 family protein expression. Together, these studies identify a promising therapeutic strategy for KRAS-mutant NSCLCs, demonstrate that BCL-2 proteins are the key mediators of the therapeutic response in this tumor type, and uncover a predictive biomarker of sensitivity.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Eukaryotic Initiation Factor-4F; Proto-Oncogene Proteins p21(ras); Protein Kinase Inhibitors; Cell Line, Tumor; TOR Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Mutation
PubMed: 37384411
DOI: 10.1172/JCI167651 -
International Journal of Biological... 2023Gastric cancer (GC) is a common malignancy and remains the fourth-leading cause of cancer-related deaths worldwide. Oncogenic potential of SDC2 has been implicated in...
Gastric cancer (GC) is a common malignancy and remains the fourth-leading cause of cancer-related deaths worldwide. Oncogenic potential of SDC2 has been implicated in multiple types of cancers, yet its role and underlying molecular mechanisms in GC remain unknown. Here, we found that SDC2 was highly expressed in GC and its upregulation correlated with poor prognosis in GC patients. Depletion of SDC2 significantly suppressed the growth and invasive capability of GC cells, while overexpressing SDC2 exerts opposite effects. Combined bioinformatics and experimental analyses substantiated that overexpression of SDC2 activated the AKT signaling pathway in GC, mechanistically through the interaction between SDC2 and PDK1-PH domain, thereby facilitating PDK1 membrane translocation to promote AKT activation. Moreover, SDC2 could also function as a co-receptor for FGF2 and was profoundly involved in the FGF2-AKT signaling axis in GC. Lastly, we revealed a mechanism on the USP14-mediated stabilization of SDC2 that is likely to contribute to SDC2 upregulation in GC tissues. Furthermore, we showed that IU1, a potent USP14 inhibitor, decreased the abundance of SDC2 in GC cells. Our findings indicate that SDC2 functions as a novel GC oncogene and has potential utility as a diagnostic marker and therapeutic target for GC.
Topics: Humans; Cell Line, Tumor; Cell Proliferation; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Proto-Oncogene Proteins c-akt; Signal Transduction; Stomach Neoplasms; Syndecan-2; Ubiquitin Thiolesterase
PubMed: 37496999
DOI: 10.7150/ijbs.84331