Metabolic enzyme PDK3 forms a positive feedback loop with transcription factor HSF1 to drive chemoresistance

Abstract

Background & Aims : Dysregulation of metabolism plays an important role in the development and progression of cancers, while the underlying mechanisms remain largely unknown. This study aims to explore the regulation and relevance of glycolysis in chemoresistance of gastric cancer. Methods: Biochemical differences between chemoresistant and chemosensitive cancer cells were determined by metabolism profiling, microarray gene expression, PCR or western blotting. Cancer cell growth in vitro or in vivo were analyzed by viability, apoptosis and nude mice assay. Immunoprecipation was used to explore the interaction of proteins with other proteins or DNAs. Results : By metabolic and gene expression profiling, we found that pyruvate dehydrogenase kinase 3 (PDK3) was highly expressed to promote glycolysis in chemoresistant cancer cells. Its genetic or chemical inhibition reverted chemoresistance in vitro and in vivo . It was transcriptionally regulated by transcription factor HSF1 (Heat shock factor 1). Interestingly, PDK3 can localize in the nucleus and interact with HSF1 to disrupt its phosphorylation by GSK3β. Since HSF1 was subjected to FBXW7-catalyzed polyubiquitination in a phosphorylation-dependent manner, PDK3 prevented HSF1 from proteasomal degradation. Thus, metabolic enzyme PDK3 and transcription factor HSF1 forms a positive feedback loop to promote glycolysis. As a result, inhibition of HSF1 impaired enhanced glycolysis and reverted chemoresistance both in vitro and in vivo . Conclusions : PDK3 forms a positive feedback loop with HSF1 to drive glycolysis in chemoresistance. Targeting this mitonuclear communication may represent a novel approach to overcome chemoresistance.

β-catenin represses miR455-3p to stimulate m6A modification of HSF1 mRNA and promote its translation in colorectal cancer

“…In cancer cells, HSF1 can drive a transcriptional program distinct from heat shock response to support malignant phenotypes [ 15 , 43 ]. For instance, HSF1 can drive the transcription of PDK3 (Pyruvate Dehydrogenase Kinase 3) to promote glycolysis in chemo-resistant cancer cells [ 44 ]. It can also recruit DNMT3a to the promoter of miR137HG and repress the biogenesis of GLS1 (Glutaminase 1)-targeting miR137, thus upregulating GLS1 expression to activate mTOR and promote cancer development [ 7 ].…”

miR‐128‐3p contributes to mitochondrial dysfunction and induces apoptosis in glioma cells via targeting pyruvate dehydrogenase kinase 1

“…In our research, except PDK1, higher PDK3 expression also was significantly associated with shorter survival period in patients with glioma (Figure d). But, to the best of our knowledge, there has been very little research on PDK3 in brain tumors, though it has been studied in other cancers, such as colon cancer and gastric cancer . PDK3 represents a worthwhile enzyme target for investigation because of its unique lack of inhibition by elevated levels of pyruvate, unlike PDK1, PDK2, and PDK4 …”

“…But, to the best of our knowledge, there has been very little research on PDK3 in brain tumors, though it has been studied in other cancers, such as colon cancer and gastric cancer. 45 PDK3 represents a worthwhile enzyme target for investigation because of its unique lack of inhibition by elevated levels of pyruvate, unlike PDK1, PDK2, and PDK4. 46 miR-128, one of the most abundant miRNAs expressed in mouse and human brain, 47 is expressed in diverse brain regions, and plays a critical role in the development and maintenance of the nervous system.…”

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…In gastric cancer, the overexpression of HSF1 has been observed in the patient samples, suggesting HSF1 to be the poor prognosis factor [91,92]. Regarding cancer cell defense mechanism, it has been shown that HSF1 forms a positive feedback loop with pyruvate dehydrogenase 3 (PDK3) to drive chemoresistance of cancers [93]. In hepatocellular carcinoma, HSF1 reduces the anti-cancer effects of epirubicin and increases the cell viability by promoting protective autophagy through upregulation of ATG4B expression [94].…”