Overexpressed Solute Carrier Family 16 Member 3 (SLC16A3, also called MCT4) plays a critical role in hypoxic cancer cell growth and proliferation, by expelling glycolysis-derived lactate across the plasma membrane. However, how SLC16A3 expression is regulated, under hypoxic conditions, is poorly understood. FBI-1, encoded by ZBTB7A, is a proto-oncoprotein. Interestingly, under hypoxic conditions, expression of SLC16A3, and hypoxia-inducible factor-1 (HIF-1), increased gradually, while FBI-1 expression decreased, suggesting a negative correlation between SLC16A3/HIF-1 and FBI-1 expression. Consequently, we hypothesized that FBI-1 might regulate SLC16A3 and/or HIF-1 expression. Transient transfection and transcription assays of SLC16A3 promoter reporter fusion constructs, oligonucleotide-pulldowns, and ChIP assays, showed that HIF-1α activates SLC16A3 by binding to a hypoxia-response element (HRE), while ectopic FBI-1 potently repressed SLC16A3, by binding to both FBI-1-response elements (FREs) and HREs, during hypoxia. Further evidence for this model was downregulation of ZBTB7A, correlated with SLC16A3 upregulation, in hypoxic colon cancer cells. We also investigated how FBI-1 expression is downregulated during hypoxia. The 5'-upstream regulatory region of ZBTB7A contains two NF-κB-binding sites and two HREs. Interestingly, hypoxia activated NF-κB (RelA/p65) and also increased its nuclear translocation. NF-κB repressed ZBTB7A by binding NF-κB-binding elements, and downregulated the repressor FBI-1, thereby increasing SLC16A3 transcription. While transcriptional repression of SLC16A3 by FBI-1 inhibited lactate efflux, repression of ZBTB7A and activation of lactate efflux by NF-κB, increased colon cancer cell growth and proliferation.
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http://dx.doi.org/10.1016/j.bbagrm.2019.06.004 | DOI Listing |
Biochem Biophys Res Commun
December 2024
Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, China. Electronic address:
ZBTB7A, alternatively referred to Pokemon, FBI-1, LRF, and OCZF, is classified as a member of POK/ZBTB protein family of transcriptional repressors. ZBTB7A binds to targeted DNA via C-terminal zinc fingers and recruits co-compression complexes through N-terminal BTB ⁄ POZ domain to impede transcription. ZBTB7A regulates a range of fundamental biological processes such as cell proliferation, differentiation and apoptosis, B- and T-lymphocyte fate determination and thymic insulin expression and self-tolerance.
View Article and Find Full Text PDFJ Cancer
June 2024
Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing City 655000, Yunnan Province, People's Republic of China.
Ferroptosis has been characterized as non-apoptotic programmed cell death and is considered a novel strategy for antitumor treatment. The factor that binds to inducer of short transcripts-1 (FBI-1) is an important proto-oncogene playing multiple roles in human malignancies and the development of resistance to therapy. However, the roles of FBI-1 in ferroptosis of endocrine independent prostate carcinoma are still unknown.
View Article and Find Full Text PDFJ Cell Biochem
March 2022
HLB Life Science, Gangnam-gu, Seoul, Republic of Korea.
The factor binding inducer of short transcripts-1 (FBI-1) is a POZ-domain Kruppel-like (POK) family of transcription factors and is known as a proto-oncogene or tumor suppressor in various carcinomas. However, the role of FBI-1 on epithelial-to-mesenchymal transition (EMT) and invasiveness in lung cancer remains unknown. Preliminarily, clinical data such as tissue microarray, Kaplan-Meier, and Oncomine were analyzed to confirm the correlation between lung cancer metastasis and FBI-1.
View Article and Find Full Text PDFFront Oncol
November 2021
Department of Hematology, PLA Rocket Force Characteristic Medical Center, Beijing, China.
The transcription suppressor factor FBI-1 (the factor that binds to inducer of short transcripts-1) is an important regulator of hepatocellular carcinoma (HCC). In this work, the results showed that FBI-1 promoted the Warburg effect and enhances the resistance of hepatocellular carcinoma cells to molecular targeted agents. Knockdown of FBI-1 its small-interfering RNA (siRNA) inhibited the ATP level, lactate productions, glucose uptake or lactate dehydrogenase (LDH) activation of HCC cells.
View Article and Find Full Text PDFDrug Des Devel Ther
September 2021
Department of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China.
Background: As a natural compound extracted from a variety of hot peppers, capsaicin has drawn increasing attention to its anti-cancer effects against multiple human cancers including breast cancer. FBI-1 is a major proto-oncogene negatively regulating the transcription of many tumor suppressor genes, and plays a vital role in tumorigenesis and progression. However, whether FBI-1 is involved in capsaicin-induced breast cancer suppression has yet to be ascertained.
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