Molecular Cancer Research最新文献_第2页

SMURF2 Facilitates GAP17 Isoform 1 Membrane Displacement to Promote Mutant p53-KRAS Oncogenic Synergy. SMURF2促进GAP17 Isoform 1膜位移，促进突变体p53-KRAS的致癌协同作用。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-06-03 DOI: 10.1158/1541-7786.MCR-24-0701

Paramita Ray, Shirish Shukla, Yaqing Zhang, Katelyn L Donahue, Derek J Nancarrow, Srimathi Kasturirangan, Sunita Shankar, Kyle Cuneo, Dafydd Thomas, Shirish M Gadgeel, Theodore S Lawrence, Marina Pasca di Magliano, Dipankar Ray

{"title":"SMURF2 Facilitates GAP17 Isoform 1 Membrane Displacement to Promote Mutant p53-KRAS Oncogenic Synergy.","authors":"Paramita Ray, Shirish Shukla, Yaqing Zhang, Katelyn L Donahue, Derek J Nancarrow, Srimathi Kasturirangan, Sunita Shankar, Kyle Cuneo, Dafydd Thomas, Shirish M Gadgeel, Theodore S Lawrence, Marina Pasca di Magliano, Dipankar Ray","doi":"10.1158/1541-7786.MCR-24-0701","DOIUrl":"10.1158/1541-7786.MCR-24-0701","url":null,"abstract":"Cooperativity between mutant p53 and mutant KRAS, although recognized, is poorly understood. In pancreatic cancer, mutant p53 induces splicing factor hnRNPK, causing an isoform switch that produces overexpression of GTPase-activating protein 17 isoform 1 (GAP17-1). GAP17-1 is mislocalized in the cytosol instead of the membrane, owing to the insertion of exon 17 encoding a PPLP motif, thus allowing mutant KRAS to remain in the GTP-bound hyperactive state. However, the role of PPLP in influencing GAP17-1 mislocalization remains unclear. We show that Smad ubiquitination regulatory factor 2 (SMURF2), a known stabilizer of mutant KRAS, interacts with GAP17-1 via the PPLP motif and displaces it from the membrane, facilitating mutant p53-mediated mutant KRAS hyperactivation. We used cell lines with known KRAS and TP53 mutations, characterized SMURF2 expression in multiple pancreatic cancer mouse models (iKras*; iKras*, p53*, and p48-Cre; Kras*), and performed single-cell RNA sequencing and tissue microarray on preclinical and clinical samples. We found that SMURF2 silencing profoundly reduces the survival of mutant TP53; KRAS-driven cells. We show that a GAP17-1 AALA mutant does not bind to SMURF2, stays in the membrane, and keeps mutant KRAS in the GDP-bound state to inhibit downstream signaling. In mouse models, mutant KRAS and SMURF2 upregulation are correlated with pancreatic intraepithelial neoplasia and ductal adenocarcinoma lesions. Furthermore, patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapy and express moderate-to-high SMURF2 show decreased overall survival (P = 0.04).Implications: In TP53 and KRAS double-mutated pancreatic cancer, SMURF2-driven GAP17-1 membrane expulsion facilitates mutant p53-KRAS oncogenic synergy.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"530-541"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT. 线粒体HSP90平行TRAP1缺失通过破坏Cys/Glu反转运蛋白SLC7A11/xCT的稳定驱动肿瘤细胞中的谷氨酰胺成瘾。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-16 DOI: 10.1158/1541-7786.MCR-24-0194

Abhinav Joshi, Li Dai, Marisa Maisiak, Sunmin Lee, Elizabeth Lopez, Takeshi Ito, Len Neckers

{"title":"Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.","authors":"Abhinav Joshi, Li Dai, Marisa Maisiak, Sunmin Lee, Elizabeth Lopez, Takeshi Ito, Len Neckers","doi":"10.1158/1541-7786.MCR-24-0194","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0194","url":null,"abstract":"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 dependency of mitochondrial respiration following glucose withdrawal. Here, we investigate how TRAP1 deletion impacts glucose metabolism and the mechanisms enabling glutamine 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 glucose oxidation remains functional, TRAP1 KO reduces overall glucose 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 glutamine retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces glutamine-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest xCT is regulated post-translationally 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 glucose uptake while preserving its metabolic fate, promoting glutamine 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 glutamine conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IL-9 promotes migratory dissemination of malignant T-cells by activating the HIF-1α-Cofilin-1 axis in cutaneous T-cell lymphoma. IL-9在皮肤t细胞淋巴瘤中通过激活HIF-1α-Cofilin-1轴促进恶性t细胞的迁移传播。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-14 DOI: 10.1158/1541-7786.MCR-24-1020

Ditipriya Mukherjee, Soumitra Marathe, Diksha Attrish, Vinanti Sawant, Bhavuk Dhamija, Sushant Kumar, Siddhi Wad, Moumita Basu, Neha Sharma, Hasmukh Jain, Steven R Barthel, Rahul Purwar

{"title":"IL-9 promotes migratory dissemination of malignant T-cells by activating the HIF-1α-Cofilin-1 axis in cutaneous T-cell lymphoma.","authors":"Ditipriya Mukherjee, Soumitra Marathe, Diksha Attrish, Vinanti Sawant, Bhavuk Dhamija, Sushant Kumar, Siddhi Wad, Moumita Basu, Neha Sharma, Hasmukh Jain, Steven R Barthel, Rahul Purwar","doi":"10.1158/1541-7786.MCR-24-1020","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-1020","url":null,"abstract":"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. Here, 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 pro-migratory and oxygen-sensing transcription factor, hypoxia inducible factor (HIF)-1α. High-throughput quantitative proteomics analyses of pseudohypoxic malignant T-cells identified the actin-modulating protein, Cofilin-1, as a pro-migratory CTCL-intrinsic target downstream of IL-9-HIF-1α signaling. Consistently, multicolor immunofluorescence staining revealed marked co-expression of Cofilin-1 with HIF-1α in both IL-9-treated human lymphoma cell lines and in patient CTCL skin biopsies compared to normal controls. Genetic knockdown of IL-9R or HIF-1α in human T-cell lymphoma lines by RNA interference significantly reduced both HIF-1α and Cofilin-1 co-expression and reversed IL-9-induced migration. Finally, pharmacological antagonism of HIF-1α activity using the FDA-designated orphan drug, echinomycin, significantly abrogated IL-9-triggered migration of both malignant T-cell lines as well as patient-derived T-cell lymphoma cells from CTCL biospecimens. Implications: Our results uncover a CTCL-intrinsic IL-9-HIF-1α-Cofilin-1 axis as a critical promoter of malignant T-cell migration. They further identify HIF-1α and Cofilin-1 as promising therapeutic targets to mitigate IL-9-induced CTCL dissemination.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel metastasis suppressor PI3KC2β is mediated by mTORC1 signalling in breast cancer. 新型转移抑制因子PI3KC2β在乳腺癌中由mTORC1信号介导。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-13 DOI: 10.1158/1541-7786.MCR-24-1045

Kanakaraju Manupati, Mingang Hao, Suhua Li, Sushma Maharjan, Jun-Lin Guan

{"title":"Novel metastasis suppressor PI3KC2β is mediated by mTORC1 signalling in breast cancer.","authors":"Kanakaraju Manupati, Mingang Hao, Suhua Li, Sushma Maharjan, Jun-Lin Guan","doi":"10.1158/1541-7786.MCR-24-1045","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-1045","url":null,"abstract":"HER2 amplification or mutation accounts for 25% of breast cancer patients that can advance to metastatic disease. Therefore, it is important to identify novel genes which mediate metastasis in HER2+ breast cancer. Here, we describe a new metastatic suppressor gene, Class II phosphatidylinositol 3-kinases (Pik3c2b), by 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 KO N418 cells increased their migration and invasion in vitro, and lung metastasis in both spontaneous and experimental metastasis assays in vivo. Analysis of breast cancer patient database and tissue samples correlated lower expression of PI3KC2β with decreased metastasis, overall and relapse-free survival. Further, PI3KC2β deletion induced activation of mTORC1 signalling, independent of affecting its kinase activity. Mechanistically, we found that PI3KC2β forms a complex with ITSN1 and raptor that could decreasing stability of raptor, and deletion of either PI3KC2β or ITSN1 led to increased raptor levels and mTORC1 signalling. Lastly, rapamycin treatment reduced migration and invasion of PI3KC2β KO tumor cells in vitro and their lung metastasis in vivo, supporting an important role of mTORC1 pathway. Together, our results identify PI3KC2β as a suppressor for HER2+ breast cancer metastasis by negatively regulating mTORC1 signalling 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.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PKCδ regulates DNA damage and cell death through a SIRT6/Nrf2-dependent antioxidant response. PKCδ通过SIRT6/ nrf2依赖的抗氧化反应调节DNA损伤和细胞死亡。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-13 DOI: 10.1158/1541-7786.MCR-24-0805

Trisiani Affandi, Angela M Ohm, Jordan T Speidel, M Cecilia Caino, Dillon P Boulton, Mary E Reyland

{"title":"PKCδ regulates DNA damage and cell death through a SIRT6/Nrf2-dependent antioxidant response.","authors":"Trisiani Affandi, Angela M Ohm, Jordan T Speidel, M Cecilia Caino, Dillon P Boulton, Mary E Reyland","doi":"10.1158/1541-7786.MCR-24-0805","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0805","url":null,"abstract":"Protein kinase C delta (PKCδ) regulates DNA repair and apoptosis, and inhibition of PKCδ provides robust radioprotection. Here we show that depletion of PKCδ increases mitochondrial ROS production and induces an endogenous antioxidant response through Nrf2, resulting in decreased basal and irradiation-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. While mitochondrial mass and membrane potential are increased in PKCδ-depleted cells, oxidative phosphorylation and the activity of electron transport chain (ETC) Complex I and Complex III are reduced, suggesting that ETC 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 irradiation 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 irradiation therapy.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

METTL3 promotes gastric cancer progression via modulation of FNTA-mediated KRAS/ERK signaling activation. METTL3通过调控fnta介导的KRAS/ERK信号激活促进胃癌进展。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-12 DOI: 10.1158/1541-7786.MCR-24-1168

Fangqi Hu, Song Zhang, Jie Chai

{"title":"METTL3 promotes gastric cancer progression via modulation of FNTA-mediated KRAS/ERK signaling activation.","authors":"Fangqi Hu, Song Zhang, Jie Chai","doi":"10.1158/1541-7786.MCR-24-1168","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-1168","url":null,"abstract":"As a vital form of post-transcriptional modification, RNA N6-methyladenosine methylation (m6A) dysregulation is usually associated with the pathogenesis of a range of diseases, including cancer, but the function and underlying mechanisms of m6A in regulating gastric cancer initiation and progression are still poorly understood. Here, we have found methytransferase like 3 (METTL3) and the level of RNA m6A modification were significantly upregulated in gastric cancerous tissues relative to their normal counterparts. In addition, higher METTL3 expression always predicted poorer outcomes for patients with gastric cancer. Methylated RNA sequencing revealed that METTL3 deposited m6A modification on FNTA (farnesyltransferase, subunit alpha) mRNA and accelerated its translation relying on YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) recognition. When METTL3 or FNTA expression was silenced in gastric cancer cells, the FNTA-mediated KRAS plasma membrane distribution was disrupted, resulting in downstream MEK/ERK signaling inactivation, which finally contributed to gastric cancer suppression in vitro and in vivo. In summary, our studies revealed a crosstalk between METTL3-mediated RNA methylation and FNTA-mediated protein modification which synergized to drive gastric cancer progression through orchestrating KRAS/ERK signaling activity. Implications: Targeting METTL3/FNTA pathway will provide an alternative to overcome the resistance of gastric cancer to canonical KRAS inhibitors.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PAX8 Interacts with the SWI/SNF Complex at Enhancers to Drive Proliferation in Ovarian Cancer. PAX8与SWI/SNF复合物增强子相互作用，促进卵巢癌的增殖。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0710

Kostianna Sereti, Anna E Russo, Ryan Raisner, Taylur P Ma, Karen E Gascoigne

{"title":"PAX8 Interacts with the SWI/SNF Complex at Enhancers to Drive Proliferation in Ovarian Cancer.","authors":"Kostianna Sereti, Anna E Russo, Ryan Raisner, Taylur P Ma, Karen E Gascoigne","doi":"10.1158/1541-7786.MCR-24-0710","DOIUrl":"10.1158/1541-7786.MCR-24-0710","url":null,"abstract":"Activation of lineage-specific gene expression programs is mediated by the recruitment of lineage-specific transcription factors and their coactivators to chromatin. The lineage factor PAX8 drives essential gene expression in ovarian cancer cells and is required for tumor proliferation. However, the molecular details surrounding cofactor recruitment and specific activation of transcription by PAX8 remain unknown. Here, we identify an important functional interaction between PAX8 and the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We show that PAX8 can recruit SWI/SNF complexes to DNA, in which they function to open chromatin and facilitate the expression of PAX8 target genes. Genetic deletion of PAX8 results in loss of SWI/SNF from PAX8-bound enhancers, loss of expression of associated target genes, and reduced proliferation. These results can be phenocopied by pharmacological inhibition of SWI/SNF ATPase activity. These data indicate that PAX8 mediates the expression of an essential ovarian cancer proliferative program in part by the recruitment of the SWI/SNF complex, highlighting a novel vulnerability in PAX8-dependent ovarian cancer. Implications: PAX8 recruits SWI/SNF complexes to enhancers to mediate the expression of genes essential for ovarian cancer proliferation.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"416-425"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epigenetic Dysregulation of Retrotransposons in Cancer. 癌症中反转录转座子的表观遗传失调。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0744

Kwok Yu Liu, Danny Leung

引用次数: 0

RNF6 Inhibits Lung Adenocarcinoma Cell Proliferation by Promoting Cyclin D2 Degradation. RNF6通过促进细胞周期蛋白D2降解抑制肺腺癌细胞增殖。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0703

Yuening Sun, Liyang Jiang, Zubin Zhang, Rongrong Zhu, Jingpei Liang, Ziyang Liu, Yuanming He, Zhenqian Huang, Chunhua Ling, Xiumin Zhou, Xinliang Mao

{"title":"RNF6 Inhibits Lung Adenocarcinoma Cell Proliferation by Promoting Cyclin D2 Degradation.","authors":"Yuening Sun, Liyang Jiang, Zubin Zhang, Rongrong Zhu, Jingpei Liang, Ziyang Liu, Yuanming He, Zhenqian Huang, Chunhua Ling, Xiumin Zhou, Xinliang Mao","doi":"10.1158/1541-7786.MCR-24-0703","DOIUrl":"10.1158/1541-7786.MCR-24-0703","url":null,"abstract":"The E3 ubiquitin ligase RING finger protein 6 (RNF6) has been widely recognized for its role in promoting tumorigenesis in multiple cancers. However, we found that it is downregulated in lung adenocarcinoma (LUAD), and the molecular rationale for this discrepancy remains unclear. In the present study, we find that RNF6, but not its ΔRING inactive form, inhibits LUAD cell proliferation and migration and sensitizes LUAD to chemotherapy. To understand the molecular mechanism, we utilize affinity purification/tandem mass spectrometry (MS-MS) to analyze RNF6-interacting proteins and find that cyclin D2 (CCND2), a key regulator of the G1-S transition in the cell cycle. RNF6 physically binds to CCND2 and mediates its K48-linked polyubiquitination and subsequent degradation. However, ΔRING RNF6 fails to mediate CCND2 for ubiquitination and degradation. Moreover, Thr280 is critically important for CCND2 stability. When Thr280 is mutated, CCND2 becomes more stable and less ubiquitinated by RNF6. Furthermore, RNF6 arrests LUAD cell cycle at the G1 phase by inhibiting the CCND2/phospho-Rb signaling pathway, which is consistent with decreased cell proliferation. Lastly, RNF6 curtails the growth of LUAD xenografts in vivo, associated with decreased CCND2 expression. Therefore, RNF6 is a novel E3 ligase of CCND2 and suppresses LUAD cell proliferation. Implications: This study reveals a novel regulation on cell-cycle transition in LUAD and suggests the RNF6/CCND2 axis may represent an alternative therapeutic target for the treatment of LUAD.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"426-437"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exome Sequencing Reveals a Sparse Genomic Landscape in Kaposi Sarcoma. 外显子组测序揭示了卡波西肉瘤的稀疏基因组景观。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-05-02 DOI: 10.1158/1541-7786.MCR-24-0373

Warren Phipps, Bhavneet Bhinder, Andrea Towlerton, Peter Mooka, James Kafeero, Matt Fitzgibbon, Olivier Elemento, Ethel Cesarman

{"title":"Exome Sequencing Reveals a Sparse Genomic Landscape in Kaposi Sarcoma.","authors":"Warren Phipps, Bhavneet Bhinder, Andrea Towlerton, Peter Mooka, James Kafeero, Matt Fitzgibbon, Olivier Elemento, Ethel Cesarman","doi":"10.1158/1541-7786.MCR-24-0373","DOIUrl":"10.1158/1541-7786.MCR-24-0373","url":null,"abstract":"Kaposi sarcoma is a frequently aggressive malignancy caused by Kaposi sarcoma herpesvirus. People with immunodeficiencies, including human immunodeficiency virus (HIV), are at increased risk for developing Kaposi sarcoma, but our understanding of the contributions of the cellular genome to Kaposi sarcoma pathogenesis remains limited. To determine if there are cellular genetic alterations in Kaposi sarcoma that might provide biological or therapeutic insights, we performed whole-exome sequencing on 78 Kaposi sarcoma tumors and matched normal control skin from 59 adults with Kaposi sarcoma (46 with HIV-associated Kaposi sarcoma and 13 with HIV-negative Kaposi sarcoma) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. We found a very low mutational burden in all but one specimen (median = 11 mutations), which is the lowest number of mutations among all 33 tumor types in The Cancer Genome Atlas. No recurrent mutations were seen, and the most commonly affected oncogenic pathway was RTK/RAS. Mutational signatures included defective DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from the same original clone. The number of genome copy alterations per genome was higher in tumors from those without HIV infection and in tumors from participants with advanced stage disease, suggesting that lesions that take longer to develop may accumulate more alterations, although the number of alterations remains low compared with other cancers. Implications: Our findings indicate that the pathogenesis of Kaposi sarcoma differs from other malignancies and that the primary driver of carcinogenesis is Kaposi sarcoma-associated herpesvirus infection and expression of viral oncogenes, rather than clonal oncogenic transformation.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"438-449"},"PeriodicalIF":4.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0