PMID- 31271899 OWN - NLM STAT- MEDLINE DCOM- 20191125 LR - 20201209 IS - 1876-4320 (Electronic) IS - 1874-9399 (Linking) VI - 1862 IP - 8 DP - 2019 Aug TI - Hypoxia-induced RelA/p65 derepresses SLC16A3 (MCT4) by downregulating ZBTB7A. PG - 771-785 LID - S1874-9399(19)30073-2 [pii] LID - 10.1016/j.bbagrm.2019.06.004 [doi] AB - 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-1alpha 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-kappaB-binding sites and two HREs. Interestingly, hypoxia activated NF-kappaB (RelA/p65) and also increased its nuclear translocation. NF-kappaB repressed ZBTB7A by binding NF-kappaB-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-kappaB, increased colon cancer cell growth and proliferation. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Choi, Seo-Hyun AU - Choi SH AD - Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMoon-Ku, Seoul 03722, Republic of Korea. FAU - Kim, Min-Young AU - Kim MY AD - Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMoon-Ku, Seoul 03722, Republic of Korea. FAU - Yoon, Young-So AU - Yoon YS AD - Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMoon-Ku, Seoul 03722, Republic of Korea. FAU - Koh, Dong-In AU - Koh DI AD - Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMoon-Ku, Seoul 03722, Republic of Korea. FAU - Kim, Min-Kyeong AU - Kim MK AD - Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMoon-Ku, Seoul 03722, Republic of Korea. FAU - Cho, Su-Yeon AU - Cho SY AD - Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMoon-Ku, Seoul 03722, Republic of Korea. FAU - Kim, Kyung-Sup AU - Kim KS AD - Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMoon-Ku, Seoul 03722, Republic of Korea. FAU - Hur, Man-Wook AU - Hur MW AD - Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMoon-Ku, Seoul 03722, Republic of Korea. Electronic address: mwhur2@yuhs.ac. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190701 PL - Netherlands TA - Biochim Biophys Acta Gene Regul Mech JT - Biochimica et biophysica acta. Gene regulatory mechanisms JID - 101731723 RN - 0 (DNA-Binding Proteins) RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Monocarboxylic Acid Transporters) RN - 0 (RELA protein, human) RN - 0 (SLC16A3 protein, human) RN - 0 (Symporters) RN - 0 (Transcription Factor RelA) RN - 0 (Transcription Factors) RN - 0 (ZBTB7A protein, human) SB - IM MH - A549 Cells MH - Cell Hypoxia MH - Cell Proliferation MH - Cell Survival MH - Colonic Neoplasms/genetics/*metabolism MH - DNA-Binding Proteins/*metabolism MH - Gene Expression Regulation, Neoplastic MH - HCT116 Cells MH - HT29 Cells MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism MH - Monocarboxylic Acid Transporters/*genetics/metabolism MH - Symporters MH - Transcription Factor RelA/*metabolism MH - Transcription Factors/*metabolism OTO - NOTNLM OT - FBI-1 OT - Hypoxia OT - MCT4 OT - NF-kappaB OT - ZBTB7A EDAT- 2019/07/05 06:00 MHDA- 2019/11/26 06:00 CRDT- 2019/07/05 06:00 PHST- 2019/02/21 00:00 [received] PHST- 2019/06/12 00:00 [revised] PHST- 2019/06/18 00:00 [accepted] PHST- 2019/07/05 06:00 [pubmed] PHST- 2019/11/26 06:00 [medline] PHST- 2019/07/05 06:00 [entrez] AID - S1874-9399(19)30073-2 [pii] AID - 10.1016/j.bbagrm.2019.06.004 [doi] PST - ppublish SO - Biochim Biophys Acta Gene Regul Mech. 2019 Aug;1862(8):771-785. doi: 10.1016/j.bbagrm.2019.06.004. Epub 2019 Jul 1.