SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle

Abstract

MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post‐transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post‐translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip‐mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri‐methylation promotes tumor glycolysis and M2‐like polarization of tumor‐associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri‐methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1‐mediated tri‐methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC.

GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression

“…Due to the Warburg effect, most solid tumors exhibit an upregulation in lactate metabolism, which leads to the acidification of the tumor microenvironment (TME). In glioma, lactate production is primarily mediated by lactate dehydrogenase A (LDHA), while the efflux is mainly facilitated by monocarboxylate transporter 1 (MCT1) [21][22][23][24][25].…”

“…The accumulation of lactate in the TME is a significant metabolic stimulus in regulating cancer progression. Studies have reported that lactate dehydrogenase A (LDHA)-mediated lactate production increases in glioma, especially in IDH wild-type glioma and monocarboxylate transporter 1 (MCT1) plays a prominent role in transmembrane transport of lactate [21][22][23][24][25]. Moreover, elevated serum lactate was reported to be correlated with glioma grade, a higher Ki-67 index and larger tumor volumes, indicating a poorer prognosis [26][27][28].…”