SMYD3 Modulates AMPK-mTOR Signaling Balance in Cancer Cell Response to DNA Damage

Abstract

Cells respond to DNA damage by activating a complex array of signaling networks, which include the AMPK and mTOR pathways. After DNA double-strand breakage, ATM, a core component of the DNA repair system, activates the AMPK-TSC2 pathway, leading to the inhibition of the mTOR cascade. Recently, we showed that both AMPK and mTOR interact with SMYD3, a methyltransferase involved in DNA damage response. In this study, through extensive molecular characterization of gastrointestinal and breast cancer cells, we found that SMYD3 is part of a multiprotein complex that is involved in DNA damage response and also comprises AMPK and mTOR. In particular, upon exposure to the double-strand break-inducing agent neocarzinostatin, SMYD3 pharmacological inhibition suppressed AMPK cascade activation and thereby promoted the mTOR pathway, which reveals the central role played by SMYD3 in the modulation of AMPK-mTOR signaling balance during cancer cell response to DNA double-strand breaks. Moreover, we found that SMYD3 can methylate AMPK at the evolutionarily conserved residues Lys411 and Lys424. Overall, our data revealed that SMYD3 can act as a bridge between the AMPK and mTOR pathways upon neocarzinostatin-induced DNA damage in gastrointestinal and breast cancer cells.

The novel SMYD3 inhibitor EM127 impairs DNA repair response to chemotherapy-induced DNA damage and reverses cancer chemoresistance

“…Recent studies on SMYD3 oncogenic role also revealed that it can be crucial for unperturbed cell division by promoting phase transition and allowing cancer cells to bypass cell cycle arrest signals [ 16 ]. Moreover, we recently showed that SMYD3 has a protective role during cell response to genotoxic stress by promoting the restoration of damaged DNA via the HR repair pathway, thereby sustaining cancer cell genomic stability and tumor progression [ 20 , 21 ]. Consistently, combined inhibition of SMYD3 and PARP, which is one of the most studied DDR targets, emerged as a promising synthetic lethality strategy in HR-proficient gastrointestinal and breast cancers expressing high levels of SMYD3 [ 20 ].…”