m6A methylation mediates LHPP acetylation as a tumour aerobic glycolysis suppressor to improve the prognosis of gastric cancer

Abstract

LHPP, a histidine phosphatase, has been implicated in tumour progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Here, we obtained GC tissues and corresponding normal tissues from 48 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. The results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein levels. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. Together, our findings suggest that LHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.

LHPP suppresses gastric cancer progression via the PI3K/AKT/mTOR signaling pathway

“…On the contrary, silencing of LHPP induced converse results. Consist with Lin et al 12 our further experiments revealed that LHPP was critically involved in the regulation of the migration and invasion of GC cells. In the light of these findings, we concluded that LHPP might inhibit the migration, invasion abilities and EMT process of GC cells.…”

“…Until recently, researchers found LHPP function as a tumor suppressor gene in multiple cancers. Nevertheless, only one article concerns the relationship between LHPP and GC progression for now 12 . From our perspective, LHPP may exert its anti-tumor effects through multiple signaling pathways.…”

“…In the current study, we focused on exploring the expression profile and potential mechanism of LHPP in GC. Lin et al 12 recently published an article claims that LHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. However, based on our bioinformatics analysis and preliminary data, we found that LHPP may suppress cell proliferation of GC via down-regulating p‑PI3K/p‑AKT expression levels.…”

Critical roles and clinical perspectives of RNA methylation in cancer

“…Functional experiments have shown that WTAP bound to the 3′‐UTR m 6 A site of HK2 enhances the glycolytic capacity of GC cells 376 . Additionally, METTL14 increases the mRNA stability of the acetylated protein LHPP, thereby attenuating glycogen synthase kinase‐3β (GSK‐3β) phosphorylation and the Wnt signaling pathway to suppress aerobic glycolysis in GC cells 377 . In PDAC, YTHDC1 augments miR‐30d expression to attenuate aerobic glycolysis by suppressing the activity of the transcription factor RUNX1 along with the promoters of SLC2A1 and HK1 378 .…”

m6A methylation: a process reshaping the tumour immune microenvironment and regulating immune evasion

“…METTL14 deficiency in renal cell carcinoma (RCC) promotes distal lung metastasis by enhancing glycolytic reprogramming [ 95 ]. However, a glycolysis-promoting role of METTL14 through the repression of LHPP, which inhibits cancer cell metabolism, has been reported in gastric cancer (GC) [ 96 ]. Other m 6 A methyltransferases, including WTAP and KIAA1429, have been found to have a glycolysis-promoting role in cancers [ 97 – 99 ].…”