LncRNA GLTC targets LDHA for succinylation and enzymatic activity to promote progression and radioiodine resistance in papillary thyroid cancer

Dysregulation of long noncoding RNAs (lncRNAs) has been associated with the development and progression of many human cancers. Lactate dehydrogenase A (LDHA) enzymatic activity is also crucial for cancer development, including the development of papillary thyroid cancer (PTC). However, whether specific lncRNAs can regulate LDHA activity during cancer progression remains unclear. Through screening, we identified an LDHA-interacting lncRNA, GLTC, which is required for the increased aerobic glycolysis and cell viability in PTC. GLTC was significantly upregulated in PTC tissues compared with nontumour thyroid tissues. High expression of GLTC was correlated with more extensive distant metastasis, a larger tumour size, and poorer prognosis. Mass spectrometry revealed that GLTC, as a binding partner of LDHA, promotes the succinylation of LDHA at lysine 155 (K155) via competitive inhibition of the interaction between SIRT5 and LDHA, thereby promoting LDHA enzymatic activity. Overexpression of the succinylation mimetic LDHA(K155E) mutant restored glycolytic metabolism and cell viability in cells in which metabolic reprogramming and cell viability were ceased due to GLTC depletion. Interestingly, GLTC inhibition abrogated the effects of K155-succinylated LDHA on radioiodine (RAI) resistance in vitro and in vivo. Taken together, our results indicate that GLTC plays an oncogenic role and is an attractive target for RAI sensitisation in PTC treatment.

Automated summary

Dysregulation of long noncoding RNAs (lncRNAs) is associated with the development and progression of human cancers. The lncRNA GLTC was identified as an interacting partner of LDHA and is required for increased glycolysis and cell viability in papillary thyroid cancer (PTC). GLTC is upregulated in PTC tissues and high expression is correlated with distant metastasis, larger tumor size, and poor prognosis. GLTC promotes LDHA enzymatic activity by inhibiting the interaction between SIRT5 and LDHA, leading to succinylation of LDHA at lysine 155 (K155). Inhibition of GLTC reverses the effects of succinylated LDHA on radioiodine (RAI) resistance. Therefore, GLTC may serve as a potential therapeutic target for enhancing RAI sensitivity in PTC treatment.