A Novel Long Non-Coding Rna as a Key Regulator of Tumor Metabolism(3/3)

Long non-coding RNA (LncR) has recently emerged as a novel biological entity contributing to oncogenesis. As such they are excellent biomarkers as well as therapy targets. We have been studying LncRs for more than five years and have several publications on this subject. Probably the most striking finding was the discovery we published in PNAS last year, of a LncR which is a coactivator of myc. As an extension of this study, we now describe a novel LncR which associates with and regulates PKM2 (pyruvate kinase M2), a gate-keeper of Warburg effect. PKM2 is a tumor-specific isoform of pyruvate kinase, responsible for pyruvate production. Its level and activity dictate the flow of pyruvate to lactate (preferred by tumor cells) or to mitochondria TCA cycle (preferred by normal cells). In another PNAS article last year, we found that PKM2 can be translocated into nucleus by association with an oncogene. This translocation converts PKM2 into a transcriptional coactivator of HIF-1a, which activates genes involved in glycolysis. Indeed, some consider the nuclear PKM2 as the oncogenic form. In this proposal, we shall characterize the new LncR which we refer to as LncR-PKM2. LncR-PKM2 retains PKM2 in the cytosol and behaves like a tumor suppressor. Detailed characterizations of this LncR represent the major aims of this proposal. The studies will be carried out in prostate cancer cells. Prostate cancer incidence has risen sharply in Taiwan in recent years. As Taiwan is approaching a super-aging society, prostate cancer will become an important health issue. At early stage, prostate cancer can be controlled by androgen-ablation therapy, which however is often transient. Castration-resistant tumors often develop at the end, resulting in mortality. As LncR-PKM2 regulates a key factor in tumor metabolism, its potential as a therapy target deserves attention.