Abstract
Pyruvate kinase M2 (PKM2) mainly catalyzes glycolysis, but it also exerts non-glycolytic functions in several cancers. While it has been shown to interact with the human papillomavirus 16 (HPV16) E7 oncoprotein, the functional significance of PKM2 in HPV-associated cervical cancer has been elusive. Here, we show that HPV16 E7 increased the expression of PKM2 in cervical cancer cells. TCGA data analyses revealed a higher level of PKM2 in HPV+ than HPV− cervical cancers and a worse prognosis for patients with high PKM2 expression. Functionally, we demonstrate that shRNA-mediated PKM2 knockdown decreased the proliferation of HPV+ SiHa cervical cancer cells. PKM2 knockdown also inhibited the E7-induced proliferation of cervical cancer cells. ML265 activating the pyruvate kinase function of PKM2 inhibited cell cycle progression and colony formation. ML265 treatments decreased phosphorylation of PKM2 at the Y105 position that has been associated with non-glycolytic functions. On the contrary, HPV16 E7 increased the PKM2 phosphorylation. Our results indicate that E7 increases PKM2 expression and activates a non-glycolytic function of PKM2 to promote cervical cancer cell proliferation.
Highlights
While cervical cancer screening methods effectively prevent cervical cancer, they are not readily available to women in developing and underdeveloped countries
We show that human papillomavirus 16 (HPV16) E7 increased pyruvate kinase M2 isoform (PKM2) expression and a high level of PKM2 was associated with a poor prognosis for cervical cancer patients
These results suggest that PKM2 may play a role in the pathogenesis of human papillomavirus (HPV)-induced cervical cancer
Summary
While cervical cancer screening methods (i.e., the Pap test and HPV test) effectively prevent cervical cancer, they are not readily available to women in developing and underdeveloped countries. The most notable HPV16 E7 targets are pRb, p107, and p130, which are commonly inactivated by DNA tumor viruses to promote S-phase entry [5]. While the expression of HPV16 E7 promotes cervical cancer in mice [6], the concurrent deletion of genes for pRb, p107, and p130 is insufficient to cause the malignancy [7]. These results indicate that other E7 targets contribute to E7-induced cervical cancer. HPV16 E7 interacts with and activates DNA-methyltransferase 1 (DNMT1), resulting in hypermethylation of anti-tumor immunity-related genes [9,10]. While it has been shown that HPV16 E7 interacts with pyruvate kinase M2 isoform (PKM2) [11], the functional significance of this interaction has not been characterized in cervical cancer
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