Molecular Cancer Research最新文献

Molecular based risk stratification of prostate cancer (PCa) holds significant potential for guiding precision therapeutic strategies. Previous studies revealed SOX4 activation drives PCa progression in PTEN deficient tumors through the PI3K-AKT signaling pathway. However, the mechanistic interplay between SOX4 and PTEN, as well as their clinical utility for prognostic stratification, remains to be elucidated. In this study, we revealed that SOX4 expression is increased in PCa patients with low PTEN levels, and the expression of SOX4 and PTEN is inversely correlated in PCa patients. Importantly, PCa patients exhibiting SOX4-high/PTEN-low (SOX4+/PTEN-) expression represent an aggressive PCa subtype associated with unfavorable prognosis. Mechanistically, we found that SOX4 downregulates PTEN protein expression at the post-transcriptional level. Through high-throughput microRNA profiling and bioinformatics analysis, we identified that SOX4 transcriptionally activates the expression of miR-106b∼25 cluster, which directly targets PTEN. Furthermore, SOX4 overexpression combined with PTEN deficiency leads hyperactivation of the PI3K-AKT pathway. Importantly, dual targeting of SOX4 and PI3K-AKT signaling effectively suppresses PCa cell proliferation, migration and invasion in vivo and in vitro. These data establish a novel SOX4/miR-106b~25/PTEN pathway model in promoting PCa progression and propose a potential therapeutic strategy for this high-risk subtype. Implications: SOX4 suppresses PTEN through the transcriptional upregulation of miR-106b~25, rendering tumors sensitive to combined inhibition of SOX4 and PI3K-AKT in prostate cancer.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis. Temozolomide (TMZ) is the most widely used chemotherapeutic agent and can significantly improve patient survival rates. However, numerous patients develop TMZ resistance, leading to limited therapeutic benefits. Therefore, it is crucial to investigate the mechanisms of TMZ resistance in patients with GBM and identify the sensitizing targets of TMZ to improve its clinical efficacy. Here, we demonstrated that acylphosphatase 2 (ACYP2) was involved in regulating the sensitivity of GBM to TMZ. ACYP2 knockdown significantly reduced the IC50 values of TMZ in GBM cells, while overexpression of ACYP2 increased their IC50 values. The combination of ACYP2 knockdown and TMZ treatment not only inhibited the malignant behavior of GBM cells in vitro but also slowed the progression of intracranial GBM in mice. Additionally, comet tail and γ-H2AX staining assays showed that ACYP2 knockdown enhanced the TMZ-induced DNA damage. Mechanistically, ACYP2 upregulates the transcription factor c-Myc to promote the transcription of its downstream target poly ADP-ribose polymerase 1 (PARP1), an important regulatory molecule for DNA damage repair, ultimately inducing TMZ resistance in GBM cells. Thus, this study demonstrated that ACYP2 is a potential therapeutic target for TMZ-resistant GBM patients. Implications: The ACYP2-driven c-Myc/PARP1 signaling axis defines a critical pathway driving temozolomide resistance and represents a translationally actionable target for therapeutic intervention in glioblastoma.

Genes encoding ETS family transcription factors are altered by chromosomal rearrangement in 60-70% of prostate cancers and nearly all Ewing sarcomas. Ewing sarcoma rearrangements result in chimeric fusion of ETS proteins to the RNA-binding protein EWSR1. Prostate cancer rearrangements result in aberrant expression of ETS proteins such as ETV1, ETV4, ETV5 or ERG that can interact with wild-type EWSR1, suggesting common mechanisms between these diseases. Here, we find that ETV1, ETV4, and ETV5 can phenocopy EWSR1::FLI1 in Ewing sarcoma cell lines. However, rescue of EWSR1::FLI1 knockdown by ERG requires an ERG mutant that disrupts interaction with PRC2. This suggests that EWSR1::ERG fusions that drive Ewing sarcoma avoid PRC2 interactions. We then identify an endogenous PRC2/FOXO1 complex and demonstrate that FOXO1 bridges the ERG/PRC2 interaction. AKT-mediated degradation of FOXO1 and subsequent loss of the ERG/PRC2 interaction provides a mechanism for ERG synergy with PTEN deletion in prostate cancer. Implications: These findings indicate that ETS transcription factors that drive prostate cancer and Ewing sarcoma utilize similar mechanisms and thus could be targeted by similar therapeutic approaches.

HER2 amplification or mutation accounts for 25% of patients with breast cancer that can advance to metastatic disease. Therefore, it is important to identify novel genes that mediate metastasis in HER2+ breast cancer. In this study, we describe a new metastatic suppressor gene, class II phosphatidylinositol 3-kinase β (Pi3kc2β), through in vivo CRISPR-Cas9 library screening of a custom-designed library targeting genes implicated in autophagy using murine HER2+ breast cancer (N418) cells. We further showed that PI3KC2β knockout N418 cells increased their migration and invasion in vitro and lung metastasis in both spontaneous and experimental metastasis assays in vivo. Analysis of databases and tissue samples from patients with breast cancer correlated lower expression of PI3KC2β with decreased metastasis, overall survival, and relapse-free survival. Further, PI3KC2β deletion induced the activation of mTORC1 signaling, independent of affecting its kinase activity. Mechanistically, we found that PI3KC2β forms a complex with intersectin 1 (ITSN1) and raptor that could be decreasing the stability of raptor, and deletion of either PI3KC2β or ITSN1 led to increased raptor levels and mTORC1 signaling. Lastly, rapamycin treatment reduced the migration and invasion of PI3KC2β knockout tumor cells in vitro and their lung metastasis in vivo, supporting an important role of the mTORC1 pathway. Together, our results identify PI3KC2β as a suppressor of HER2+ breast cancer metastasis by negatively regulating mTORC1 signaling by affecting its complex formation with ITSN1 and raptor.

Implications: Our findings revealed PI3KC2β as a new metastasis suppressor for HER2+ breast cancer, which might serve as a potential diagnostic and therapeutic target for the disease.

Protein kinase C δ (PKCδ) regulates DNA repair and apoptosis, and inhibition of PKCδ provides robust radioprotection. In this study, we show that depletion of PKCδ increases mitochondrial reactive oxygen species (ROS) production and induces an endogenous antioxidant response through nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in decreased basal and irradiation (IR)-induced DNA damage and cell death. Radioprotection by PKCδ depletion can be reversed with the free radical scavenger, N-acetyl-L-cysteine, indicating an essential role for the antioxidant response. Whereas mitochondrial mass and membrane potential are increased in PKCδ-depleted cells, oxidative phosphorylation and the activity of electron transport chain complex I and complex III are reduced, suggesting that electron transport chain dysfunction is the source of the increased mitochondrial ROS. The antioxidant response induced by PKCδ depletion is mediated through Sirtuin 6 (SIRT6) and Nrf2. Increased mitochondrial ROS and Nrf2 activation are reversed in PKCδ/SIRT6 double knockdown cells, indicating a central role for SIRT6 in PKCδ-regulated DNA repair and cell death. Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing IR therapy.

Implications: Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing IR therapy.

TRAP1, the mitochondrial isoform of HSP90, has emerged as a key regulator of cancer cell metabolism, yet the mechanisms by which it rewires nutrient utilization remain poorly understood. We previously reported that TRAP1 loss increases glutamine (Gln) dependency of mitochondrial respiration following glucose (Glc) withdrawal. In this study, we investigate how TRAP1 deletion impacts Glc metabolism and the mechanisms enabling Gln retention to support mitochondrial respiration via reductive carboxylation and the oxidative TCA cycle. TRAP1 knockout (KO) in bladder and prostate cancer cells recapitulates the carbon source-specific metabolic rewiring previously observed. Stable isotope tracing reveals that although Glc oxidation remains functional, TRAP1 KO reduces overall Glc uptake and its contribution to glycolysis and the pentose phosphate pathway. This effect is consistent across multiple cell lines. Concurrently, TRAP1-deficient cells exhibit increased Gln retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces Gln-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest that xCT is regulated posttranslationally via protein stability. Notably, xCT suppression does not trigger ferroptosis, indicating a selective adaptation rather than induction of cell death. Together, our findings suggest that TRAP1 loss decreases Glc uptake while preserving its metabolic fate, promoting Gln conservation through xCT downregulation to maintain mitochondrial respiration without inducing ferroptosis.

Implications: These results reveal a TRAP1-dependent mechanism of metabolic rewiring in cancer cells and identify xCT-mediated Gln conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.

Cutaneous T-cell lymphoma (CTCL) is a multistage disease characterized by rapid dissemination of malignant T lymphocytes from skin lesions to visceral organs and bone marrow. The cytokine IL-9 and its receptor (IL-9R) are aberrantly overexpressed in CTCL lesions and function to enhance tumor cell survival. In this study, we uncovered a critical new role for IL-9 as a potent inducer of migration of malignant T cells. Stimulation of IL-9R-expressing T-cell lymphoma cells with IL-9 induced a pseudohypoxic cellular state by elevating downstream levels of the promigratory and oxygen-sensing transcription factor hypoxia-inducible factor (HIF)-1α. High-throughput quantitative proteomic analyses of pseudohypoxic malignant T cells identified the actin-modulating protein cofilin-1 (CFL-1) as a promigratory CTCL-intrinsic target downstream of IL-9-HIF-1α signaling. Consistently, multicolor immunofluorescence staining revealed marked coexpression of CFL-1 with HIF-1α in both IL-9-treated human lymphoma cell lines and in patient CTCL skin biopsies compared with normal controls. Genetic knockdown of IL9R or HIF1A in human T-cell lymphoma lines by RNAi significantly reduced both HIF-1α and CFL-1 coexpression and reversed IL-9-induced migration. Finally, pharmacologic antagonism of HIF-1α activity using the FDA-designated orphan drug echinomycin significantly abrogated IL-9-triggered migration of both malignant T-cell lines and patient-derived T-cell lymphoma cells from CTCL biospecimens.

Implications: Our results uncover a CTCL-intrinsic IL-9-HIF-1α-CFL-1 axis as a critical promoter of malignant T-cell migration. They further identify HIF-1α and CFL-1 as promising therapeutic targets to mitigate IL-9-induced CTCL dissemination.

Bone metastasis continues to be the greatest challenge in treating patients with prostate cancer despite ongoing research. In bone, prostate cancer tumors hijack normal bone remodeling processes to drive cancer progression. However, it is unclear how these interactions drive bone-metastatic prostate cancer growth in the bone environment. To understand the mechanisms associated with bone-metastatic prostate cancer regulation of mesenchymal stem cells (MSC), we previously identified that bone-metastatic prostate cancer induces MSC expression of the pro-inflammatory chemokine CXCL8 and its mouse functional homologue Cxcl1. To date, there has been little to no information about the role of CXCL1/8 in MSC biology and its impact in the tumor-bone environment. Using genetic deletion of Cxcl1, we discovered a novel role for Cxcl1/8 in regulating MSC osteoblast differentiation, such that targeted deletion of Cxcl1 enhanced MSC osteoblastogenesis. Despite the osteogenic nature of prostate cancer, co-injection of Cxcl1 knockout (KO) MSCs with bone-metastatic prostate cancer in bone significantly suppressed tumor growth compared with co-injection with scrambled control (non-targeting) MSCs, even in the presence of three times more prostate cancer to MSCs. Furthermore, bulk RNA sequencing revealed immune response pathways, both in Cxcl1-KO MSCs and bone-metastatic prostate cancer tumors containing Cxcl1-KO MSCs. In support of this, Cxcl1-KO MSCs reduced immature neutrophils in the bone environment, while increasing monocytes. These findings demonstrate the importance of MSC-derived Cxcl1 in the bone microenvironment and highlight the importance of Cxcl1 in bone-metastatic prostate cancer progression.

Implications: MSC-derived Cxcl1 regulates prostate cancer progression in bone.

SFTA1P is a pseudogene-derived long noncoding RNA and has become a master regulator in tumor carcinogenesis and progression processes. SFTA1P has been reported as a potential diagnostic and prognostic biomarker in non-small cell lung cancer (NSCLC). The downregulation of SFTA1P in tumor tissue has been associated with poor prognosis; however, the detailed molecular mechanism and biological functions still need to be investigated. We demonstrated that SFTA1P inhibited the growth and metastasis of NSCLC in vitro and in vivo. SFTA1P had dual functions in the cytoplasm and nucleus: In the cytoplasm, SFTA1P can serve as a "sponge" for miR-665 to increase the expression level of TGFBR2; in the nucleus, SFTA1P can bind the positive transcription elongation factor b and subsequently inhibit the transcriptase activity of RNA polymerase II. The regulation of TGFBR2 and positive transcription elongation factor b via SFTA1P depends on its subcellular localization, which was affected by the status of the N6-methyladenosine RNA modification of SFTA1P. Our research demonstrated that the candidate tumor-suppressor SFTA1P is extensively involved in NSCLC, which may offer novel insights into NSCLC oncogenesis.

Implications: SFTA1P is downregulated in NSCLC and had dual functions in the cytoplasm and nucleus.

The small G-protein Rac1 is a central player in cancer progression and metastatic dissemination. Rac1 has been established as a bona fide effector of receptor tyrosine kinases, acting as a signaling node for motility, invasiveness, mitogenesis, and gene expression. Previous studies demonstrated that Rac1 is hyperactivated in aggressive cellular models of prostate cancer. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of Rac1 results in impaired proliferation and migration of prostate cancer cells. Rac1-null cells display profound alterations in transcriptional programs, particularly those associated with cell adhesion and extracellular matrix regulation. Combined expression profiling and unbiased RNAi screening of Rac1 guanine nucleotide exchange factors identified VAV2 as the foremost mediator EGF-induced GTP loading onto Rac1 in prostate cancer cells. Depletion of VAV2 from prostate cancer cells significantly reduced their proliferative and migratory capacities without affecting the expression of Rac1-regulated genes, suggesting that VAV2 controls a discrete subset of Rac1-dependent cellular responses. IHC assessment in human prostate biopsies showed significant VAV2 overexpression in tumor areas. Bioinformatic analysis revealed a strong correlation between VAV2 expression and poor clinical prognosis. In addition to uncovering a prominent role for VAV2-Rac1 as an effector pathway mediating EGFR-driven proliferative and migratory responses in prostate cancer cells, our findings underscore the potential prognostic value of VAV2 in human prostate cancer progression.

Implications: This study highlights the central role of VAV2 in prostate cancer cell proliferation and migration, as well as its potential prognostic value in disease progression.