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six1 enhances aerobic glycolysis and progression in cervical cancer through ENO1

HUMAN CELL 2025年第3期38卷 1-15页

作者： Liu, Xuelian Ren, Hang Wang, Anjin Liang, Ziyan Min, Su Yao, Shijie Wan, Shimeng Gao, Yang Wang, Hua Cai, Hongbing Wuhan Univ Zhongnan Hosp Dept Gynecol Oncol 169 Donghu Rd Wuhan Peoples R China Hubei Key Lab Tumor Biol Behav Wuhan Peoples R China Hubei Canc Clin Study Ctr Wuhan Peoples R China

Cervical cancer is a significant threat to women's health, and its incidence in China has been increasing in recent years. Treating advanced and recurrent cervical cancer has become increasingly challenging, highlighting the urgent need to identify new therapeutic targets for this disease. six1 is associated with cell proliferation, metastasis, and chemoresistance in various human malignancies. six1 overexpression in cervical cancer tissues has been linked to increased clinical stage and lymph node metastasis;however, the regulatory function of six1 in cervical cancer remains largely unexplored. In this study, we found that six1 promotes cervical cancer cell proliferation, invasion, and migration by enhancing glucose metabolism. Additionally, six1 was shown to influence the glycolytic process in cervical cancer by upregulating GLUT1, PFK1, PGK1, ENO1, and PKM2 expression. Furthermore, we identified a binding site for six1 in the ENO1 promoter region, demonstrating that six1 has a regulatory effect. These results suggest that six1 regulates proliferation and glucose metabolism in cervical cancer cells by promoting the transcription of key glycolytic enzymes, such as ENO1. Understanding this regulatory mechanism is crucial for identifying potential therapeutic targets for cervical cancer.

关键词： Cervical cancer Glycolysis six1 ENO1

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Transcriptional Regulation of De Novo Lipogenesis by six1 in Liver Cancer Cells

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ADVANCED SCIENCE 2024年第41期11卷 e2404229页

作者： Li, Ling Zhang, Xiujuan Xu, Guang Xue, Rui Li, Shuo Wu, Shumeng Yang, Yuanjun Lin, Yanni Lin, Jing Liu, Guoxiao Gao, Shan Zhang, Youzhi Ye, Qinong Beijing Inst Biotechnol Beijing 100071 Peoples R China Capital Med Univ Sch Tradit Chinese Med Beijing 100069 Peoples R China Beijing Inst Pharmacol & Toxicol Beijing 100850 Peoples R China Shanxi Med Univ Sch Basic Med Sci Taiyuan 030000 Peoples R China Peoples Liberat Army Gen Hosp Med Ctr 4 Dept Clin Lab Beijing 100037 Peoples R China Peoples Liberat Army Gen Hosp Med Ctr 1 Dept Gen Surg Med Beijing 100853 Peoples R China Southeast Univ Zhongda Hosp Adv Inst Life & Hlth Sch Life Sci & Technol Nanjing 210096 Peoples R China

De novo lipogenesis (DNL), a hallmark of cancer, facilitates tumor growth and metastasis. Therapeutic drugs targeting DNL are being developed. However, how DNL is directly regulated in cancer remains largely unknown. Here, transcription factor sine oculis homeobox 1 (six1) is shown to directly increase the expression of DNL-related genes, including ATP citrate lyase (ACLY), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1), via histone acetyltransferases amplified in breast cancer 1 (AIB1) and lysine acetyltransferase 7 (HBO1/KAT7), thus promoting lipogenesis. six1 expression is regulated by insulin/lncRNA DGUOK-AS1/microRNA-145-5p axis, which also modulates DNL-related gene expression as well as DNL. The DGUOK-AS1/microRNA-145-5p/six1 axis regulates liver cancer cell proliferation, invasion, and metastasis in vitro and in vivo. In patients with liver cancer, six1 expression is positively correlated with DGUOK-AS1 and SCD1 expression and is negatively correlated with microRNA-145-5p expression. DGUOK-AS1 is a good predictor of prognosis. Thus, the DGUOK-AS1/microRNA-145-5p/six1 axis strongly links DNL to tumor growth and metastasis and may become an avenue for liver cancer therapeutic intervention.

关键词： de novo lipogenesis noncoding RNA six1 transcription factor tumor growth and metastasis

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Molecular characterization of Secreted in Xylem 1 (six1) gene of Fusarium oxysporum causing wilt of potato (Solanum tuberosum)

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PLANT PATHOLOGY 2024年第7期73卷 1847-1858页

作者： Ghosal, Debraj Datta, Bejoysekhar Univ Kalyani Dept Bot Mycol & Plant Pathol Res Lab Nadia 741235 West Bengal India

Deciphering effector genes of plant-pathogenic fungi is key to understanding their role in pathogenicity because acquisition of such genes through horizontal transfer may result in emergence of new pathogenic races. A full-length (837 bp) six1 gene has been cloned and sequenced from the genome of Fusarium oxysporum FPo isolated from roots of wilted potatoes in West Bengal, India. The isolate was identified based on conidial morphology and sequencing of the 28S rDNA and elongation factor 1 alpha gene. Koch's postulates established that the isolate could incite wilting in potato plants. The six Gene Expression 1 gene (Sge1) was amplified from the isolate and compared with that of other wilt-causing F. oxysporum isolates. The six1 gene had no intron and it encoded 278 amino acids, with a calculated molecular weight of 30.6 kDa, estimated isoelectric point 5.66 and theoretical extinction coefficient of 57,410 M-1 cm(-1). Multiple sequence alignment of six1 amino acid sequences showed that the length of six1 varied among F. oxysporum formae speciales and different isolates of the same forma specialis. The predicted secondary structure of FPosix1 contained four alpha-helices and 14 beta-sheets. Its predicted tertiary structure showed 92% query coverage and 67.37% identity with the template of the six1 protein of F. oxysporum f. sp. lycopersici PDB code: 7t69. The QMEAN score of this model was -2.53 and the model was validated using the Ramachandran Phi/Psi plot. Structure analysis of the effector protein will be helpful to identify its specific function and recognition by the host resistance protein.

关键词： Fusarium wilt homology modelling phylogenetic analysis potato SGE1 six1

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Manzamine A: A promising marine-derived cancer therapeutic for multi-targeted interactions with E2F8, six1, AR, GSK-3β, and V-ATPase - A systematic review

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EUROPEAN JOURNAL OF PHARMACOLOGY 2025年 990卷 177295页

作者： Mishan, Mohammad Amir Choo, Yeun-Mun Winkler, Jeffery Hamann, Mark T. Karan, Dev Brown Canc Ctr Dept Urol 505 S Hancock St Louisville KY 40202 USA Univ Malaya Fac Sci Dept Chem Kuala Lumpur 50603 Malaysia Univ Penn Dept Chem Philadelphia PA USA Med Univ South Carolina Coll Pharm Dept Drug Discovery & Biomed Sci & Publ Hlth Charleston SC USA Med Univ South Carolina Coll Med Hollings Canc Ctr Charleston SC USA

Manzamine A, a natural compound derived from various sponge genera, features a beta-carboline structure and exhibits a range of biological activities, including anti-inflammatory and antimalarial effects. Its potential as an anticancer agent has been explored in several tumor models, both in vitro and in vivo, showing effects through mechanisms such as cytotoxicity, regulation of the cell cycle, inhibition of cell migration, epithelial-tomesenchymal transition (EMT), autophagy, and apoptosis through multi-target interactions of E2F transcriptional factors, ribosomal S6 kinases, androgen receptor (AR), six1, GSK-3 beta, v-ATPase, and p53/p21/p27 cascades. This systematic review evaluates existing literature on the potential application of this marine alkaloid as a novel cancer therapy, highlighting its promising ability to inhibit cancer cell growth while causing minimal side effects.

关键词： Manzamine A six1 AR GSK-3 beta V-ATPases Cell cycle regulation Cancer therapy

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six1 as a Novel Immunohistochemical Marker in the Differential Diagnosis of Rhabdomyosarcoma

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FETAL AND PEDIATRIC PATHOLOGY 2023年第5期42卷 723-734页

作者： Ehinger, Daniel Frostberg, Hanna Larsson, Sofia Gisselsson, David Univ Hosp Dept Pathol Med Serv Lab Med Lund Sweden Lund Univ Dept Clin Sci Div Oncol Lund Sweden Lund Univ Dept Lab Med Div Clin Genet Lund Sweden Klin Patol Solvegatan 25 S-22185 Lund Sweden

Background: Differential diagnosis of rhabdomyosarcoma (RMS) is challenging. Sineoculis homeobox homolog 1 (six1) is an oncogene involved in skeletal muscle differentiation. We compared protein expression patterns of six1 in RMS and its most common differential diagnoses. Methods: six1 immunohistochemistry in 36 RMS and in 33 tumors from seven differential diagnostic subtypes were evaluated. The fraction of six1 positive tumor cells was scored by three independent observers. Results: A majority (75%) of the evaluated RMS expressed six1 in at least 50% of tumor cells and all except one RMS had more than 25% positive tumor cells. Neuroblastoma had less than 1% six1 positive tumor cells. Gonadoblastoma, malignant rhabdoid tumor, and Ewing sarcoma had 10% or less positive tumor cells. Pleuropulmonary blastoma exhibited 26-50% positive tumor cells and synovial sarcoma >50% positive cells. Conclusion: six1 immunohistochemistry is positive in most RMS, and occasionally in some tumors within the differential diagnoses of RMS.

关键词： six1 Rhabdomyosarcoma E-RMS A-RMS

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SENP3 mediates deSUMOylation of six1 to promote prostate cancer proliferation and migration

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CELLULAR & MOLECULAR BIOLOGY LETTERS 2024年第1期29卷 146页

作者： Shao, Zhenlong Liu, Shutong Sun, Wenshuang Zhuang, Xuefen Yin, Shusha Cheng, Ji Xia, Xiaohong Liao, Yuning Liu, Jinbao Huang, Hongbiao Guangzhou Med Univ Affiliated Canc Hosp Guangzhou Inst Canc Res Guangzhou 510095 Peoples R China Guangzhou Med Univ Sch Basic Med Sci Guangzhou Municipal & Guangdong Prov Key Lab Prot Guangzhou 511436 Guangdong Peoples R China

BackgroundSentrin/SUMO-specific protease 3 (SENP3) is essential to regulate protein stability and function in normal and cancer cells. Nevertheless, its role and action mechanisms in prostate cancer (PCa) remain elusive. Thus, clarification of SENP3's involvement and the SUMOylation process in PCa is pivotal for discovering potential targets and understanding SUMOylation *** viability, EdU staining, live cell imaging, and cell cycle assays were used to determine proliferation of PCa cells. Transwell and wound-healing assays were used to detect migration of PCa cells. The interaction between SENP3 and six1 was determined by co-immunoprecipitation, western blotting, and immunofluorescence assays. Xenograft models established on NOD-SCID mice were used to evaluate in vivo effects post SENP3 knockdown. Immunohistochemistry was performed to investigate the expression of SENP3 in PCa *** study found that SENP3 is highly expressed in PCa cell lines and tissues from PCa patients. Overexpressed SENP3 is associated with metastatic malignancy in PCa. Various in vivo and in vitro experiments confirmed that SENP3 promotes the proliferation and migration of PCa. In addition, SENP3 interacts with the SD domain of six1 and mediates its deSUMOylation and protein stability. Lys154 (K154) is required for the SUMOylation of six1. More importantly, SENP3 promotes the malignancy of PCa through the regulation of *** unravel the significant role of SENP3 in regulating protein stability of six1 and progression of PCa, which may deepen our understanding of the SUMOylation modification and provide a promising target for management of metastatic PCa.

关键词： SUMOylation SENP3 six1 Prostate cancer Tumor progression

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six1 expression and its clinicopathological significance: difference between classic and follicular variant papillary thyroid carcinoma

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THYROID RESEARCH 2024年第1期17卷 1-10页

作者： Khalil, Elzahraa Ibrahim Issa, Ahmed S. Kamal, Rehab M. Minia Univ Fac Med Dept Pediat El Minia Egypt Minia Univ Fac Med Radiol Dept Al Minya Egypt

BackgroundPapillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, representing the majority of thyroid cancer cases. Most patients with PTC have an excellent prognosis following treatment, yet approximately 10% face mortality within ten years, primarily due to lymph node metastasis (LNM) or local recurrence. The six1 gene, a member of the six gene superfamily, encodes a transcription factor integral to the development of certain tissues during embryogenesis. The impact of six1 in different subtypes of PTC has not been studied *** purpose of this study was to investigate the expression of six1 protein in PTC and to explore its relationship with clinical behavior in two subtypes of PTC: classic PTC (C-PTC) and follicular variant PTC (FV-PTC).Materials and methodsUsing immunohistochemistry, the study analyzed 125 primary PTC cases, including 85 cases of C-PTC and 40 cases of *** study found significant positive associations between high six1 expression and several adverse clinical features across the PTC samples. High six1 expression was linked with increased tumor size, multifocal tumors, LNM, high-grade tumor features, advanced tumor stage, lymphovascular invasion, perineural invasion, and extrathyroidal extension (ETE). Within the classic PTC subgroup, high six1 expression showed significant positive correlations with Tumor size (P = 0.04), Multifocality (P = 0.02) and High-grade features (P = 0.03). In the follicular variant subgroup, high six1 expression was significantly associated with Lymph node metastasis (LNM) (P = 0.001), Lymphovascular invasion (P = 0.03), ETE (P = 0.003) and tumor stage (P = 0.007).ConclusionsThe findings of this study indicate that six1 expression is a marker of poor prognosis in PTC, suggesting that its high expression is linked with more aggressive tumor characteristics and advanced disease stages. Importantly, the impact of six1 expression varies between C-PTC and FV-PTC, predic

关键词： six1 Papillary thyroid carcinoma Classic PTC Follicular variant PTC Immunohistochemistry

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Transcriptomic analysis reveals the role of six1 in mouse cranial neural crest patterning and bone development

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DEVELOPMENTAL DYNAMICS 2023年第10期252卷 1303-1315页

作者： Baxi, Aparna Jourdeuil, Karyn Cox, Timothy C. Clouthier, David E. Tavares, Andre L. P. George Washington Univ Dept Anat & Cell Biol Sch Med & Hlth Sci Washington DC USA Univ Missouri Kansas City Dept Oral & Craniofacial Sci Kansas City MO USA Univ Colorado Dept Craniofacial Biol Anschutz Med Campus Aurora CO USA Univ Missouri Kansas City Dept Pediat Kansas City MO USA George Washington Univ Dept Anat & Cell Biol Sch Med & Hlth Sci Washington DC 20037 USA

BackgroundGenetic variants of the transcription factor six1 and its co-factor EYA1 underlie 50% of Branchio-oto-renal syndrome (BOR) cases. BOR is characterized by craniofacial defects, including malformed middle ear ossicles leading to conductive hearing loss. In this work, we expand our knowledge of the six1 gene regulatory network by using a six1-null mouse line to assess gene expression profiles of E10.5 mandibular arches, which give rise to the neural crest (NC)-derived middle ear ossicles and lower jaw, via bulk RNA sequencing. ResultsOur transcriptomic analysis led to the identification of 808 differentially expressed genes that are related to translation, NC cell differentiation, osteogenesis, and chondrogenesis including components of the WNT signaling pathway. As WNT signaling is a known contributor to bone development, we demonstrated that six1 is required for expression of the WNT antagonist Frzb in the mandibular arch, and determined that six1 expression results in repression of WNT signaling. ConclusionOur results clarify the mechanisms by which six1 regulates the development of NC-derived craniofacial elements that are altered in six1-associated disorders. In addition, this work identifies novel genes that could be causative to this birth defect and establishes a link between six1 and WNT signaling during patterning of NC cells.

关键词： Branchio-oto-renal syndrome craniofacial defects hearing loss six1 transcriptional regulation

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FOXC2-induced circCASK aggravates colorectal cancer progression by upregulating six1 expression

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IUBMB LIFE 2023年第8期75卷 659-672页

作者： Zou, Junwei Huang, Yong Chen, Yuan Wu, Zhaoying Xie, Hao Zhou, Hailang Xing, Chungen Soochow Univ Dept Gastrointestinal Surg Affiliated Hosp 2 Suzhou Jiangsu Peoples R China Wannan Med Coll Dept Gastrointestinal Surg Affiliated Hosp 2 Wuhu Anhui Peoples R China Nantong Tumor Hosp Dept Gen Surg Nantong Jiangsu Peoples R China Lianshui Peoples Hosp Dept Gastroenterol Huaian Jiangsu Peoples R China

Colorectal cancer (CRC) ranks as the most common gastrointestinal solid carcinoma globally. Substantial evidence has established a pivotal role for circular RNAs (circRNAs) in CRC progression. In this study, differentially expressed circRNAs were analyzed based on a public dataset (GSE126094) and elevated expression of circCASK (hsa_circ_0001917) was validated in CRC. Moreover, increased circCASK was also confirmed in CRC patients. Functionally, circCASK knockdown led to a significant decrease in CRC cell growth and attenuated cell migration and invasion. Similarly, circCASK knockdown markedly attenuated tumor growth in vivo. Mechanistically, circCASK sponged miR-1271-5p and enhanced sine oculis homeobox homolog 1 (six1) expression. More importantly, both six1 overexpression and miR-1271-5p knockdown could reverse the cellular behavior inhibition induced by circCASK knockdown. Furthermore, six1 was most strongly and positively linked with Wnt/beta-catenin signaling pathways, circCASK triggered Wnt/beta-catenin signaling through the miR-1271-5p/six1 axis, and FOXC2 transcriptionally induced circCASK expression. In conclusion, circCASK induced by FOXC2 accelerated CRC progression through the miR-1271-5p/six1 axis, thus providing an interesting insight into CRC tumorigenesis.

关键词： circCASK colorectal cancer FOXC2 miR-1271-5p six1

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LRRC75A-AS1 delivered by M2 macrophage exosomes promotes cervical cancer progression via enhancing six1 expression

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CANCER SCIENCE 2023年第6期114卷 2634-2649页

作者： Sui, Hong-Ying Cui, Xiu-Ying Shi, Cai-Xia Yan, Zhi-Peng Li, Hu-Cheng Wang, Fang Cent South Univ Affiliated Canc Hosp Xiangya Sch Med Changsha Hunan Peoples R China Cent South Univ Hunan Canc Hosp Dept Gynecol Oncol Changsha Hunan Peoples R China Peoples Hosp Turpan City Dept gyneacol Turpan Peoples R China Cent South Univ Affiliated Canc Hosp Xiangya Sch Med 283 Tongzipo Rd Changsha 410013 Peoples R China Cent South Univ Hunan Canc Hosp Dept Gynecol Oncol 283 Tongzipo Rd Changsha 410013 Peoples R China

We aimed to investigate potential roles of LRRC75A-AS1 delivered by M2 macrophage exosomes in inducing cervical cancer progression. We demonstrated LRRC75A-AS1 was highly expressed in exosomes from M2 macrophages which could be absorbed by Hela cells. M2 macrophage-derived exosomes promoted Hela cell proliferation, migration, invasion, and EMT process by delivering LRRC75A-AS1. LRRC75A-AS1 directly targeted and suppressed miR-429 in Hela cells. The regulation of cell functions by exosomes from LRRC75A-AS1-overexpressing M2 macrophages was abrogated by miR-429 mimics. miR-429 directly targeted and repressed six1 expression. six1 overexpression alleviated the modulation of cellular functions and STAT3/MMP-9 signaling by miR-429 mimics. Also, miR-429 overexpression or six1 silence repressed tumor formation and metastasis in nude mice, which was mitigated by exosomes from LRRC75A-AS1-overexpressing M2 macrophages. In conclusion, LRRC75A-AS1 delivered by M2 macrophage exosomes repressed miR-429 to elevate six1 expression and promote cervical cancer progression through activating the STAT3/MMP-9 axis.

关键词： cervical cancer exosomes LRRC75A-AS1 M2 macrophages miR-429 six1

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