CARM1 promotes gastric cancer progression by regulating TFE3 mediated autophagy enhancement through the cytoplasmic AMPK-mTOR and nuclear AMPK-CARM1-TFE3 signaling pathways

Abstract

Background The role of CARM1 in tumors is inconsistent. It acts as an oncogene in most cancers but it inhibits the progression of liver and pancreatic cancers. CARM1 has recently been reported to regulate autophagy, but this function is also context-dependent. However, the effect of CARM1 on gastric cancer (GC) has not been studied. We aimed to explore whether CARM1 was involved in the progression of GC by regulating autophagy. Methods The clinical values of CARM1 and autophagy in GC were evaluated by immunohistochemistry and qRT–PCR. Transmission electron microscopy, immunofluorescence and western blotting were employed to identify autophagy. The role of CARM1 in GC was investigated by CCK-8, colony formation and flow cytometry assays in vitro and a xenograft model in vivo. Immunoprecipitation assays were performed to determine the interaction of CARM1 and TFE3. Results CARM1 was upregulated in clinical GC tissues and cell lines, and higher CARM1 expression predicted worse prognosis. CARM1 enhanced GC cell proliferation, facilitated G1-S transition and inhibited ER stress-induced apoptosis by regulating autophagy. Importantly, treatment with a CARM1 inhibitor rescued the tumor-promoting effects of CARM1 both in vitro and in vivo. Furthermore, we demonstrated that CARM1 promoted TFE3 nuclear translocation to induce autophagy through the cytoplasmic AMPK-mTOR and nuclear AMPK-CARM1-TFE3 signaling pathways. Conclusion CARM1 promoted GC cell proliferation, accelerated G1-S transition and reduced ER stress-induced apoptosis by regulating autophagy. Mechanistically, CARM1 triggered autophagy by facilitating TFE3 nuclear translocation through the AMPK-mTOR and AMPK-CARM1-TFE3 signaling pathways.

CARM1 drives mitophagy and autophagy flux during fasting-induced skeletal muscle atrophy

“…Moreover, fasting altered CARM1 biology within the context of early markers of autophagy signaling at threshold of atrophy in human skeletal muscle. Collectively, this study supports and extends earlier work characterizing CARM1 expression and function in human skeletal muscle in vivo, as well as demonstrates that CARM1 is a powerful regulator of autophagy [ 24 , 33 , 34 , 38 , 39 ], particularly in skeletal muscle [ 6 , 15 , 21 , 22 ], along with mitophagic and atrophic processes critical for the maintenance and remodeling of muscle mass.…”

“…In contrast, levels of p-FOXO3 (Ser253) in mKO animals were similar between fed and fasted muscle. Moreover, we analyzed the phosphorylation status of AMPK downstream targets FOXO3 (Ser413) and FOXO3 (Ser588) [ 32 ], as CARM1 and AMPK coregulate autophagic and atrophic signaling [ 15 , 24 , 33 , 34 ]. Relative to the WT fed group, carm1 deletion resulted in a significant 1.6-fold increase in p-FOXO3 (Ser413) levels under fed and fasted conditions.…”

Inhibition of CARM1 suppresses proliferation of multiple myeloma cells through activation of p53 signaling pathway

“…CARM1, an important target in cancer, is closely related to tumor cell proliferation. CARM1-KD promotes the proliferation of lung cancer cells [ 27 ], and the down-regulation of CARM1 significantly inhibits the proliferation of gastric cancer cells [ 28 ]. In contrast, the proliferation role of CARM1 in MM and the mechanism of its occurrence have been rarely reported.…”

The Role of YAP-JNK in the Mitophagy, Migration, and Invasion of Gastric Cancer

“…Autophagy is a conserved intracellular catabolic process that maintains physiological balance by removing damaged organelles. 5 Autophagy is usually activated in the absence of nutrients and has been linked to diseases as diverse as neurodegenerative diseases, inflammation, and cancer. 6 Autophagy can regulate the occurrence and metastasis of tumours, and targeting autophagy is a basic strategy in cancer therapy.…”