Ammonium tetrathiomolybdate (ATTM) has been used in
breast cancer therapy for
copper chelation, as elevated
copper promotes
tumor growth. ATTM is also an identified H2S donor and endogenous H2S facilitates VitB12-induced
S-adenosylmethionine (SAM) generation, which have been confirmed in
m6A methylation and
lung cancer development. The
m6A modification was recently shown to participate in
lung adenocarcinoma (LUAD) progression. These conflicting analyses of ATTM's anticancer vs. H2S's
carcinogenesis suggest that H2S should not be ignored during LUAD's treatment with ATTM. This study was aimed to explore ATTM's effects on LUAD cells and mechanisms associated with H2S and
m6A. It was found that treatment with ATTM inhibited cell growth at high concentrations, while enhanced cell growth at low concentrations in three LUAD cell lines (A549, HCC827, and PC9). However, another
copper chelator triethylenetetramine, without H2S releasing activity, was not found to induce cell growth. Low ATTM concentrations also elevated
m6A content in A549 cells. Analysis of differentially expressed genes in TCGA cohort indicated that
m6A writer METTL3 and reader YTHDF1 were upregulated while eraser FTO was downregulated in LUAD tissues, consistent with the findings of
protein expression in patient tissues. ATTM treatment of A549 cells significantly increased METTL3/14 and YTHDF1 while decreased FTO expression. Furthermore, inhibition of
m6A with shMETTL3
RNA significantly attenuated eukaryotic translation
initiation factor (eIF) expressions in A549 cells. Correlation analysis indicated that small nuclear ribonucleic
protein PRPF6 was positively expressed with YTHDF1 in LUAD tissues. Knockdown of YTHDF1 partially blocked both basal and ATTM-induced PRPF6 expression, as well as A549 cell growth. Lastly, ATTM treatment not only raised intracellular H2S content but also upregulated H2S-producing
enzymes. Exogenous H2S application mimicked ATTM's aforementioned effects, but the effects could be weakened by
zinc-induced H2S scavenging. Collectively, H2S impedes ATTM-induced anticancer effects through YTHDF1-dependent PRPF6
m6A methylation in
lung adenocarcinoma cells.