TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

Abstract

Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin‐responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non‐histone, well‐known tumor suppressor protein 53 (p53) and co‐regulates a wide array of metabolic genes. Among these, the p53‐responsive carbohydrate metabolic genes Tp53‐induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose‐mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short‐term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA‐Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53‐mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.

Genome-wide allele and haplotype-sharing patterns suggested one unique Hmong–Mein-related lineage and biological adaptation history in Southwest China

“…MUC22 is upregulated or downregulated in lung adenocarcinoma and squamous cell carcinoma [ 39 ] and is also seen in childhood asthma Expression [ 40 ]. TCF19 may act as a susceptibility gene for non-small cell carcinoma in the Chinese populations, interacting with tumor suppressor protein ( P53 ) and playing a role in various metabolic pathways, including cancer and diabetes [ 41 ]. KHDRBS2 has a regulatory role in microenvironmental permeability, hereditary retinopathy, and cancer [ 42 , 43 ].…”

Immunotherapeutic Value of Transcription Factor 19 (TCF19) Associated with Renal Clear Cell Carcinoma: A Comprehensive Analysis of 33 Human Cancer Cases

“…This potentially indicates that TCF19 is correlated to the responses of inflammation and cell cycle progression [ 11 , 16 ]. The genes associated with the TCF family regulate innate immunity and adaptive immunity [ 19 , 20 ]. It has been previously reported that TCF1 helps achieve a balance between the CD8+ T cells by regulating the internal IL-10 signaling pathway which in turn influences immunotherapy [ 21 ].…”

Epigenetic regulation of Fructose‐1,6‐bisphosphatase 1 by host transcription factor Speckled 110 kDa during hepatitis B virus infection

“…Lactate production of a cell was estimated by a kit‐based method (Abcam; Cat no. ab65331) following manufacturer's protocol as described previously [67]. Briefly, ~ 2 × 10 6 cells were harvested, washed with ice‐cold PBS, resuspended in lactate assay buffer and homogenized immediately.…”