Zhao Kunming, Wang Xingwen, Zhao Dong, Lin Qingyu, Zhang Yi, Hu Ying
School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, China 150001.
School of Public Health, Qingdao University, Qingdao, China 266071.
Research (Wash D C). 2022 Jul 5;2022:9854904. doi: 10.34133/2022/9854904. eCollection 2022.
Lactic acid acidifies the tumor microenvironment and promotes multiple critical oncogenic processes, including immune evasion. Pyruvate kinase M2 (PKM2) is a dominant form of pyruvate kinase (PK) expressed in cancers that plays essential roles in metabolic reprograming and lactate production, rendering it as an attractive therapeutic target of cancer. However, the mechanism underlying PKM2 regulation remains unclear. Here, we show that long noncoding RNA (lncRNA) HIF-1 inhibitor at transcription level (HITT) inhibits lactate production in a PKM2-dependent manner. Mechanistically, it physically interacts with PKM2 mapped to a region that has been involved in both dimer (less-active) and tetramer (more-active) formation, inhibiting PKM2 oligomerization and leading to dramatic reduction of PK activity. Under glucose starvation, HITT was reduced as a result of miR-106 induction, which subsequently facilitates PKM2 oligomerization and increases vulnerability to apoptosis under glucose starvation stress. In addition, the interaction also reduces lactate secretion from cancer cells, which subsequently polarizes macrophages toward an M2-like anti-inflammatory phenotype and thus possibly contributes to immune escape . This study highlights an important role of an lncRNA in regulating PKM2 activity and also reveals a metabolic regulatory effect of PKM2 on macrophage polarization.
乳酸可酸化肿瘤微环境并促进包括免疫逃逸在内的多个关键致癌过程。丙酮酸激酶M2（PKM2）是癌症中表达的丙酮酸激酶（PK）的主要形式，在代谢重编程和乳酸生成中起关键作用，使其成为有吸引力的癌症治疗靶点。然而，PKM2调控的潜在机制仍不清楚。在此，我们表明转录水平的长链非编码RNA（lncRNA）HIF-1抑制剂（HITT）以PKM2依赖的方式抑制乳酸生成。从机制上讲，它与定位到参与二聚体（活性较低）和四聚体（活性较高）形成区域的PKM2发生物理相互作用，抑制PKM2寡聚化并导致PK活性显著降低。在葡萄糖饥饿条件下，由于miR-106的诱导，HITT减少，这随后促进PKM2寡聚化并增加在葡萄糖饥饿应激下对凋亡的易感性。此外，这种相互作用还减少癌细胞的乳酸分泌，这随后使巨噬细胞向M2样抗炎表型极化，从而可能导致免疫逃逸。这项研究突出了lncRNA在调节PKM2活性中的重要作用，也揭示了PKM2对巨噬细胞极化的代谢调节作用。
