PI-103

The online version contains supplementary material available at 10.1007/s13205-025-04323-4.

Dysregulated autophagy has been implicated in the pathogenesis of numerous diseases, including cancer. Despite extensive research on the underlying mechanisms of autophagy, the involvement of long non-coding RNAs (lncRNAs) remains poorly understood. Here, we demonstrate that a previously identified lncRNA, HITT (HIF-1α inhibitor at the translation level), is closely associated with biological processes such as autophagy through unbiased bioinformatic analysis. Subsequent studies demonstrate that HITT is increased by several autophagic stimuli, including PI-103, a potent inhibitor of PI3K and mTOR. This is caused by a reduction in the binding between HITT and AGO2, resulting in a reduction in the activity of miR-205 towards HITT degradation. Increased HITT then binds to a key autophagy protein, Autophagy-related 5 (ATG5), and inhibits autophagosome formation by preventing the formation of the ATG12-ATG5-ATG16L1 complex. This results in HITT sensitizing PI-103-mediated cell death both in vitro and in vivo in nude mice by attenuating protective autophagy. The data presented herein demonstrate that HITT is a newly identified RNA regulator of autophagy and that it can be used to sensitize the colon cancer response to cell death by blocking the protective autophagy.