The m6A-induced lncRNA CASC8 promotes proliferation and chemoresistance via upregulation of hnRNPL in esophageal squamous cell carcinoma

Abstract

Long noncoding RNAs (lncRNAs) are dysregulated in many cancers. Here, we identified the molecular mechanisms of lncRNA Cancer Susceptibility Candidate 8 (CASC8) in promoting the malignancy of esophageal squamous cell carcinoma (ESCC). CASC8 was highly overexpressed in ESCC tissues and upregulation of CASC8 predicted poor prognosis in ESCC patients. Moreover, CASC8 decreased the cisplatin sensitivity of ESCC cells and promoted ESCC tumor growth in vivo. Mechanistically, CASC8 interacted with heterogeneous nuclear ribonucleoprotein L (hnRNPL) and inhibited its polyubiquitination and proteasomal degradation, thus stabilizing hnRNPL protein levels and activating the Bcl2/caspase3 pathway. Additionally, AlkB Homolog 5, RNA demethylase (ALKBH5)-mediated m6A demethylation stabilized the CASC8 transcript, resulting in CASC8 upregulation. Taken together, these findings identified an oncogenic function of CASC8 in the progression of ESCC, which suggest that CASC8 might become a potential prognostic biomarker in ESCC.

New insights into the interaction between m6A modification and lncRNA in cancer drug resistance

“…Mechanistically, the upregulation of CASC8 in ESCC was associated with ALKBH5-mediated m6A demethylation via regulating its stability. 152 Cervical cancer (CC) is the fourth leading cause of cancer-related death in women, with poor clinic outcomes. 153 The epidemiological patterns of CC are often coined a 'disease of disparity', because of the significant disparity in incidence and mortality between low-income and middle-income countries.…”

“…LncRNA CASC8 was significantly upregulated in ESCC tissues, accompanied with upregulated cell proliferation and cisplatin sensitivity. Mechanistically, the upregulation of CASC8 in ESCC was associated with ALKBH5‐mediated m6A demethylation via regulating its stability 152 …”

“…Mechanistically, the upregulation of CASC8 in ESCC was associated with ALKBH5‐mediated m6A demethylation via regulating its stability. 152 …”

Novel insights into the interplay between m6A modification and programmed cell death in cancer

“…Mechanistically, ABL is stabilized by METTL3-mediated m6A modification and subsequently binds to APAF1 to block the apoptosome assembly and caspase-9/3 activation, thereby leading to increased sensitivity to chemotherapy 90 . For chemoresistance in ESCC, the highly overexpressed ALKBH5-induced lncRNA CASC8 activate the Bcl2/Caspase3 pathway to decrease the cisplatin sensitivity of ESCC and promote tumor development 91 .…”

Biological and pharmacological roles of m6A modifications in cancer drug resistance

“…YTHDF2-mediated endoribonucleolytic cleavage of m 6 A-modified circASK1 also contributed to LUAD gefitinib resistance [119]. ALKBH5-mediated m 6 A demethylation stabilizes CASC8 transcription, ultimately leading to cisplatin resistance in ESCC [120]. Furthermore, YTHDF2 increased CDKN1B mRNA degradation in an m 6 A-dependent manner, which promoted intrahepatic cholangiocarcinoma (ICC) progression and reduced sensitivity to cisplatin treatment [121].…”