A Novel Translational Activation of HIF1α Promotes Pancreatic Cancer Growth Through Glycolytic Reprogramming

See “BZW1 facilitates glycolysis and promotes tumor growth in pancreatic ductal adenocarcinoma through potentiating eIF2α phosphorylation,” by Li Z, Ge Y, Dong J, et al, on page 1256. See “BZW1 facilitates glycolysis and promotes tumor growth in pancreatic ductal adenocarcinoma through potentiating eIF2α phosphorylation,” by Li Z, Ge Y, Dong J, et al, on page 1256. Pancreatic cancer is characterized by the presence of prominent desmoplasia forming a dense, fibrous microenvironment that compresses vessels and generates high interstitial pressure, resulting in limited tumor angiogenesis and poor drug penetration. The lack of vascularization prompts tumor cells to rewire their metabolic programs to survive the stress conditions, such as hypoxia and nutrient deprivation, by activating key oncogenes or switching off tumor suppressors.1Halbrook C.J. Lyssiotis C.A. Employing metabolism to improve the diagnosis and treatment of pancreatic cancer.Cancer Cell. 2017; 31: 5-19Google Scholar,2McDonald P.C. Chafe S.C. Brown W.S. et al.Regulation of pH by carbonic anhydrase 9 mediates survival of pancreatic cancer cells with activated KRAS in response to hypoxia.Gastroenterology. 2019; 157: 823-837Google Scholar The Warburg effect, known as enhanced glucose uptake and glycolysis to produce lactate in the aerobic condition, is a hallmark of pancreatic cancer metabolism.3Liberti M.V. Locasale J.W. The Warburg effect: how does it benefit cancer cells?.Trends Biochem Sci. 2016; 41: 211-218Google Scholar Tumor cells with metabolic stress undergo fine tuning of gene expression to adapt to the environment by up-regulating the expression of oncogenes, such as HIF1α, MYC, and other glycolytic genes.4Ying H. Kimmelman A. Lyssiotis C. et al.Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.Cell. 2012; 149: 656-670Google Scholar, 5Erkan M. Kurtoglu M. Kleeff J. The role of hypoxia in pancreatic cancer: a potential therapeutic target?.Expert Rev Gastroenterol Hepatol. 2016; 10: 301-316Google Scholar, 6Dang C. Le A. Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities.Clin Cancer Res. 2009; 15: 6479-6483Google Scholar Hypoxia-inducible factor 1α (HIF1α) plays an important role in promoting pancreatic tumor cell progression.7Spivak-Kroizman T.R. Hostetter G. Posner R. et al.Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer.Cancer Res. 2013; 73: 3235-3247Google Scholar, 8Huang C. Li Y. Li Z. et al.LIMS1 Promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by enhancing HIF1A protein translation.Clin Cancer Res. 2019; 25: 4091-4103Google Scholar, 9Zhao T. Ren H. Li J. et al.LASP1 is a HIF1alpha target gene critical for metastasis of pancreatic cancer.Cancer Res. 2015; 75: 111-119Google Scholar, 10Zhao X. Gao S. Ren H. et al.Hypoxia-inducible factor-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-bundling protein fascin.Cancer Res. 2014; 74: 2455-2464Google Scholar, 11Zhao T. Jin F. Xiao D. et al.IL-37/ STAT3/ HIF-1alpha negative feedback signaling drives gemcitabine resistance in pancreatic cancer.Theranostics. 2020; 10: 4088-4100Google Scholar HIF1α triggers the secretion of the SHH (sonic hedgehog) ligand, leading to increased paracrine Gli activation and the formation of collagen 1 and fibronectin by fibroblasts in pancreatic cancer.7Spivak-Kroizman T.R. Hostetter G. Posner R. et al.Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer.Cancer Res. 2013; 73: 3235-3247Google Scholar Moreover, HIF1α forms a positive feedback loop with LIM and senescent cell antigen-like–containing domain protein 1 (LIMS1), which increases HIF1α translation by activating AKT/mTOR (mechanistic target of rapamycin) signaling and up-regulates GLUT1 expression to promote the Warburg effect in pancreatic cancer cells against oxygen and glucose deprivation.8Huang C. Li Y. Li Z. et al.LIMS1 Promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by enhancing HIF1A protein translation.Clin Cancer Res. 2019; 25: 4091-4103Google Scholar Furthermore, HIF1α is known to directly activate transcription of LASP1 and Facsin, resulting in the extracellular matrix and cytoskeleton remodeling to enhance tumor metastasis.9Zhao T. Ren H. Li J. et al.LASP1 is a HIF1alpha target gene critical for metastasis of pancreatic cancer.Cancer Res. 2015; 75: 111-119Google Scholar,10Zhao X. Gao S. Ren H. et al.Hypoxia-inducible factor-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-bundling protein fascin.Cancer Res. 2014; 74: 2455-2464Google Scholar Zhao et al11Zhao T. Jin F. Xiao D. et al.IL-37/ STAT3/ HIF-1alpha negative feedback signaling drives gemcitabine resistance in pancreatic cancer.Theranostics. 2020; 10: 4088-4100Google Scholar reported that HIF1α is involved in the down-regulation of human interleukin-37 transcription, an anti-inflammatory and immunosuppressive cytokine, and promoted pancreatic cancer cell chemoresistance, migration, and progression. Consequently, an interleukin-37/STAT3/HIF1α-negative feedback signaling was revealed to drive gemcitabine resistance in pancreatic cancer. HIF1α is degraded under normoxia condition by binding to the VHL (Von Hippel-Lindau), while is stabilized under hypoxia condition and translocates to the nucleus to regulate the expression of genes involved in carcinogenesis and tumor growth.12Tanimoto K. Makino Y. Pereira T. et al.Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein.EMBO J. 2000; 19: 4298-4309Google Scholar Together, as a metabolic switch under hypoxic conditions, the rapid and critical regulation of HIF1α on the downstream signals is indispensable for pancreatic cancer progression. However, previous studies were focused mainly on the downstream molecular events of HIF1α and Myc; the mechanism of how the expression of HIF1α and MYC are selectively maintained under the metabolic stress are poorly understood. In this issue of Gastroenterology, Li et al13Li Z. Ge Y. Dong J. et al.BZW1 facilitates glycolysis and promotes tumor growth in pancreatic ductal adenocarcinoma through potentiating eIF2α phosphorylation.Gastroenterology. 2022; 162: 1256-1271Google Scholar elucidated a novel translational activation of HIF1α, which promoted glycolysis in pancreatic cancer. They demonstrated a new function of basic leucine zipper and W2 domain-containing protein 1 (BZW1) acting as an adaptor for protein kinase R–like endoplasmic reticulum kinase (PERK) to facilitate the phosphorylation of eIF2α and promote internal ribosome entry site (IRES)-dependent translation of HIF1α and c-Myc under metabolic stress. PERK is a serine/threonine transmembrane ER kinase, which phosphorylates eIF2α and inhibits the exchange of GDP for GTP and ultimately reduces the translation initiation.14Harding H. Zhang Y. Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase.Nature. 1999; 397: 271-274Google Scholar Stress-induced phosphorylation of eIF2α and IRES-dependent translation leads to global protein synthesis reduction and selected translation increase, which play important roles in tumor progression.15Holmes B. Lee J. Landon K.A. et al.Mechanistic rarget of rapamycin (mTOR) inhibition synergizes with reduced internal ribosome entry site (IRES)-mediated translation of cyclin D1 and c-MYC mRNAs to treat glioblastoma.J Biol Chem. 2016; 291: 14146-14159Google Scholar,16Miao B. Wei C. Qiao Z. et al.eIF3a mediates HIF1alpha-dependent glycolytic metabolism in hepatocellular carcinoma cells through translational regulation.Am J Cancer Res. 2019; 9: 1079-1090Google Scholar Thus, the IRES-dependent regulation at the initiation step of protein translation has been recognized as one of the central mechanisms to alter gene expression patterns rapidly in response to internal or external stimuli for cells and organisms.17Barbosa C. Peixeiro I. Romao L. Gene expression regulation by upstream open reading frames and human disease.PLoS Genet. 2013; 9e1003529Google Scholar Scaffold proteins are regulators of many key signaling pathways and cellular activities by serving as a docking site to tether multiple protein partners to enhance specific binding and facilitate signal transduction. The chromatin-associated protein SETD5 was reported as a scaffold protein of a co-repressor complex, including histone deacetylase 3 (HDAC3) and a histone methyltransferase G9a, to silence gene expression in drug resistance pathways, and serve as a major driver of pancreatic cancer resistance to MEK1/2 inhibition by reprogramming the cellular responses.18Wang Z. Hausmann S. Lyu R. et al.SETD5-coordinated chromatin reprogramming regulates adaptive resistance to targeted pancreatic cancer therapy.Cancer Cell. 2020; 37: 834-849.e13Google Scholar The functions of eIF2α were also reported to be regulated by other scaffold proteins. Choy et al19Choy M.S. Yusoff P. Lee I.C. et al.Structural and functional analysis of the GADD34:PP1 eIF2α phosphatase.Cell Rep. 2015; 11: 1885-1891Google Scholar demonstrated that the stress-induced protein growth-arrest– and DNA-damage–induced transcript 34 (GADD34) scaffolds serine/threonine protein phosphatase 1 (PP1) and eIF2α together to dephosphorylate eIF2α for restoring normal cellular protein synthesis after stress. BZW1 was previously reported to be an eIF5 mimic protein that binds to eIF2α and promotes uORF-dependent translation of ATF4, a key pro-oncogenic transcriptional factor.20Kozel C. Thompson B. Hustak S. et al.Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation.Nucleic Acids Res. 2016; 44: 8704-8713Google Scholar In their study, Li et al13Li Z. Ge Y. Dong J. et al.BZW1 facilitates glycolysis and promotes tumor growth in pancreatic ductal adenocarcinoma through potentiating eIF2α phosphorylation.Gastroenterology. 2022; 162: 1256-1271Google Scholar revealed that BZW1 acts as a scaffold protein for PERK and promotes the phosphorylation of eIF2α (Figure 1). As a consequence, HIF1α and c-Myc, the key regulators of glycolytic and biomolecule synthesis pathways, are translationally activated in an IRES-dependent manner, which is required for pancreatic cancer growth and metastasis. This study provides a new perspective for the master gene translational regulation under the unique hypoxic tumor microenvironment in pancreatic cancer. In Li et al’ s study,13Li Z. Ge Y. Dong J. et al.BZW1 facilitates glycolysis and promotes tumor growth in pancreatic ductal adenocarcinoma through potentiating eIF2α phosphorylation.Gastroenterology. 2022; 162: 1256-1271Google Scholar PERK and p-eIF2α inhibitors, but not BZW1 inhibitors, were used to determine whether BZW1 regulated eIF2α phosphorylation through PERK. However, the complete elimination of eIF2α phosphorylation and PERK activity could cause toxicity to normal cells due to the suppression of the global protein translation, therefore, the use of more specific BZW1 inhibitors or small molecule inhibitors of IRES-mediated translation may bring exclusive benefit to decode the detailed roles BZW1 played in regulating protein translation in pancreatic cancer cells. In summary, the current study demonstrated that BZW1 promoted glycolysis through translational regulation of HIF1α and c-Myc, suggesting a new function of BZW1 in pancreatic cancer metabolic reprogramming and tumor progression. Enhanced glycolysis had been revealed to be associated with the synthesis of many other macromolecules, such as lipids and proteins. To decipher the detailed roles BZW1 played in the regulation of key enzymes in the metabolic reprogramming, additional metabolic pathways, including fatty acids and amino acids, warrant further investigation. Taken together, this novel BZW1/HIF1α translational regulatory mechanism provides a better understanding of the biology of pancreatic cancer and developing targeted therapies for this devastating disease. BZW1 Facilitates Glycolysis and Promotes Tumor Growth in Pancreatic Ductal Adenocarcinoma Through Potentiating eIF2α PhosphorylationGastroenterologyVol. 162Issue 4PreviewResearchers found that BZW1, an oncogene in pancreatic cancer, enhances glycolysis and promotes pancreatic cancer growth under conditions of metabolic stress. Full-Text PDF