Lnc5q21.2, a novel long intergenic RNA, sensitizes colorectal cancer cells to ATR inhibitor by activating Wnt pathway

Background and objectives Colorectal cancer (CRC) is still the leading cause of cancer-related death. With the recognizing the importance of long non-coding RNA (LncRNA) in development and cancer, it is urgently to identify new LncRNA and understand the mechanism to develop novel therapeutic strategies. Methods Nine CRC cell lines, 52,146 and 285 cases of normal colorectal mucosa, adenoma and CRC samples were utilized. Northern blot, rapid amplification of cloned cDNA ends, RNA pulldown, Mass spectrum, RNA immunoprecipitation, CRISPR/Cas9, fluorescence in situ hybridization assays and xenograft mice model were employed. Results Lnc5q21.2 is identified to be a novel long intergenic non-coding RNA and its full length is 668 nt. Lnc5q21.2 is mainly located in cell nucleus and its expression is regulated by N 6 -methyladenine (6mA) modification. Compared to adjacent tissue, the levels of Lnc5q21.2 were increased significantly in CRC samples ( P < 0.001), with a progression tendency from noncancerous colorectal mucosa, adjacent tissue, adenoma to CRC samples ( P < 0.001). Lnc5q21.2 highly expression is associated with alcohol consumption and poor prognosis (both P < 0.05). Lnc5q21.2 promotes cell proliferation, migration, invasion and cell cycle progression. Lnc5q21.2 activates Wnt signaling by interacting with homeobox A10 (HOXA10) and down regulating empty spiracles homeobox 2 expression. Further study demonstrates that Lnc5q21.2 promotes DNA damage repair by enhancing ATR signaling. Lnc5q21.2 sensitizes CRC cells to ATR inhibitor both in vitro and in vivo . Conclusions Lnc5q21.2 is a novel lncRNA. Lnc5q21.2 promotes ATR pathway by activating Wnt signaling via interacting with HOXA10. Lnc5q21.2 sensitizes CRC cells to ATR inhibitor both in vitro and in vivo .