LncRNA GLTC targets LDHA for succinylation and enzyme activity to promote differentiated thyroid cancer progression and radioiodine resistance

Abstract Long noncoding RNA (lncRNA) dysregulation has been associated with the development and progression of many human cancers. Lactate dehydrogenase A (LDHA) enzyme activity is also crucial for cancer development, including that of differentiated thyroid cancer (DTC). Nevertheless, it remains unclear whether specific lncRNAs can regulate LDHA activity in cancer progression. Through screening, we identified an LDHA-interacting lncRNA, GLTC, which is required for increased aerobic glycolysis and cell proliferation in DTC. GLTC was significantly upregulated in DTC tissues compared with nontumorous thyroid tissues. High expression of GLTC was correlated with progressive histologic type, extent of distant metastases, larger tumor size, and poorer prognosis. Mass spectrometry revealed that GLTC, as a binding partner of LDHA, promotes the succinylation of LDHA on lysine-155 (K155) via its competitive inhibition of the interaction between SIRT5 and LDHA, thereby promoting LDHA enzymatic activity. Overexpression of the succinylation-mimic LDHAK155E mutant restored glycolytic metabolism and proliferation in cells that had ceased metabolic reprogramming and proliferation due to GLTC depletion. Interestingly, GLTC inhibition abrogated the effects of succinylated LDHA K155 on radioiodine (RAI) resistance in vitro and in vivo. Taken together, our results indicate that GLTC plays an oncogenic role and is an attractive RAI sensitization target for the treatment of DTC.