Human papillomavirus type 16 (HPV16) is responsible for most cancers attributable to HPV infection and naturally occurring variants of the HPV16 E6 oncoprotein predispose individuals to varying risk for developing cancer. Population studies by us and others have demonstrated that the common Asian-American E6 (AAE6) variant is a higher risk factor for cervical cancer than the E6 of another common variant, the European prototype (EPE6). However, a complete understanding of the molecular processes fundamental to these epidemiological findings is still lacking. Our previously published functional studies of these two E6 variants showed that AAE6 had a higher immortalization and transformation potential than EPE6. Proteomic analysis revealed markedly different protein patterns between these variants, especially with respect to key cellular metabolic enzymes. Here, we tested the Warburg effect and hypoxia signalling (hallmarks of cancer development) as plausible mechanisms underlying these observations. Lactate and glucose production were enhanced in AAE6-transduced keratinocytes, likely due to raised levels of metabolic enzymes, but independent of hypoxia-inducible factor 1 alpha (HIF-1α) activity. The HIF-1α protein level and activity were elevated by AAE6 in hypoxic conditions, leading to a hypoxia-tolerant phenotype with enhanced migratory potential. The deregulation of HIF-1α was caused by the AAE6 variant's ability to augment mitogen-activated protein kinase/extracellular related kinase signalling. The present study reveals prominent underlying mechanisms of the AAE6's enhanced oncogenic potential.