The N6-methyladenosine (m⁶A) RNA modification can regulate autophagy to modulate the growth and development of tumors, but the mechanism of m6A modification for the regulation of autophagy in hepatocellular carcinoma cells (HCC) remains unclear. In the study, the knockdown of the Wilms’ tumor 1-associating protein (WTAP) was made in HCC to study the correlation between m6A modification and autophagy. A fluorescent confocal microscopy analysis showed that the knockdown of WTAP could facilitate the autophagy of HCC. A Western blot analysis showed that the level of p-AMPK was decreased in WTAP-knockdown HCC cells. Additionally, LKB1, the upstream kinase of AMPK, was regulated by WTAP and it could mediate the phosphorylation of AMPK in an m6A-dependent manner. Further studies revealed that the knockdown of WTAP could reduce the level of LKB1 mRNA with m6A. This could result in the increased stability of LKB1 mRNA to promote its expression. The knockdown of WTAP could upregulate the level of autophagy and inhibit HCC proliferation. However, the overexpression of WTAP could resist autophagic cell death.

Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

Chemo and radiation therapies are the most commonly used therapies for cancer, but they can induce DNA damage, resulting in the apoptosis of host cells. DNA double-stranded breaks (DSBs) are the most lethal form of DNA damage in cells, which are constantly caused by a wide variety of genotoxic agents, both environmentally and endogenously. To maintain genomic integrity, eukaryotic organisms have developed a complex mechanism for the repair of DNA damage. Researches reported that many cellular long noncoding RNAs (lncRNAs) were involved in the response of DNA damage. The roles of lncRNAs in DNA damage response can be regulated by the dynamic modification of N6-adenosine methylation (m6A). The cellular accumulation of DNA damage can result in various diseases, including cancers. Additionally, lncRNAs also play roles in controlling the gene expression and regulation of autophagy, which are indirectly involved with individual development. The dysregulation of these functions can facilitate human tumorigenesis. In this review, we summarized the origin and overview function of lncRNAs and highlighted the roles of lncRNAs involved in the repair of DNA damage.