Increased autophagy activity suppresses hyperglycemia-related colorectal cancer tumorigenesis both in vitro and in vivo.

Hyperglycemia contributes to recurrence, poor survival, and drug resistance in colorectal cancer (CRC) patients. Overexpression of G9a (euchromatic histone-lysine N-methyltransferase 2, EHMT2), together with decreased autophagy activity, has been implicated in promoting CRC tumorigenesis and chemoresistance. Here, we demonstrate that high glucose (25 mM) enhances proliferation, focus formation, and migration of CRC cells, while concurrently suppressing autophagy activity. Importantly, pharmacological induction of autophagy increases CRC cell sensitivity to chemotherapeutic agents (5-fluorouracil and oxaliplatin) and attenuates high glucose-induced tumorigenic behaviors. Analysis of CRC patient specimens and data from the TCGA COAD database revealed that LC3, an autophagy marker, is elevated in tumor tissues compared to adjacent normal tissues, and that high LC3 mRNA expression correlates with poor overall survival. Furthermore, enhancing autophagy via the autophagy inducer rapamycin significantly suppressed high glucose-induced tumor formation in a CRC xenograft mouse model. In addition, we identified niclosamide (NC), a repurposed antihelminthic agent, and its derivative niclosamide ethanolamine (NEN), as potential G9a inhibitors and autophagy inducers. NEN dose-dependently suppressed high glucose-activated oncogenic signaling pathways, including β-catenin, c-Myc, STAT3, G9a, and cyclin D1, while restoring autophagy activity. Collectively, our in vitro and in vivo findings strongly support that enhancing autophagy represents a multifaceted strategy to alleviate hyperglycemia, inhibit G9a-mediated signaling, increase chemosensitivity, and suppress high glucose-driven CRC tumorigenesis.