Hypoxia-induced RelA/p65 derepresses SLC16A3 (MCT4) by downregulating ZBTB7A

Area of Science:

• Molecular Biology
• Cancer Research
• Cellular Metabolism

Background:

• Overexpressed Solute Carrier Family 16 Member 3 (SLC16A3, MCT4) drives hypoxic cancer cell growth by exporting lactate.
• Regulation of SLC16A3 under hypoxia is not well understood, despite its critical role in cancer proliferation.
• FBI-1 (encoded by ZBTB7A) is a proto-oncoprotein, and its expression inversely correlates with SLC16A3 and HIF-1 under hypoxia.

Purpose of the Study:

• To elucidate the regulatory mechanism of SLC16A3 expression under hypoxic conditions.
• To investigate the role of FBI-1 and NF-κB in the transcriptional regulation of SLC16A3 and ZBTB7A.
• To understand how these molecular events contribute to colon cancer cell growth and proliferation.

Main Methods:

• Transient transfection and transcription assays using SLC16A3 promoter reporter constructs.
• Oligonucleotide-pulldown and Chromatin Immunoprecipitation (ChIP) assays to determine protein-DNA interactions.
• Analysis of NF-κB (RelA/p65) activation, nuclear translocation, and its binding to regulatory elements of ZBTB7A.

Main Results:

• Hypoxia-inducible factor-1 (HIF-1α) activates SLC16A3 transcription by binding to a hypoxia-response element (HRE).
• FBI-1 represses SLC16A3 transcription by binding to both FBI-1-response elements (FREs) and HREs.
• Hypoxia activates NF-κB, which represses ZBTB7A (and thus FBI-1) expression, leading to increased SLC16A3 transcription and lactate efflux, promoting cancer cell proliferation.

Conclusions:

• NF-κB-mediated repression of ZBTB7A (FBI-1) is a key mechanism for SLC16A3 upregulation under hypoxia.
• The interplay between HIF-1α, FBI-1, and NF-κB regulates lactate efflux and colon cancer cell growth.
• Targeting this pathway could offer novel therapeutic strategies for hypoxic colon cancers.