Fig. 4
From: The chromatin-associated RNAs in gene regulation and cancer
CaRNAs form R-loops and the m6A modification on caRNAs in cancer. A The accumulation of R-loops resulted in genomic instability, and DNA damage has dual roles in cancer. The deletion of the DNA damage response protein RNF168 or transcription coactivator BRD4 blocks the unwinding of DNA and RNA heterozygous strands on the genome, leading to the accumulation of R-loops on the cancer cell genome and tumor repression. The BRD4 inhibitor JQ1 can also lead to similar accumulation of R-loops. Mutation of the tumor suppressor DDX41 causes aberrant R-loop accumulation, and genomic instability stimulates the inflammatory response and AML progression. Similarly, lncRNA HOTTIP-formed R-loops can recruit the CTCF/cohesin complex at TAD boundaries, which promotes Wnt/β-catenin transcription and accelerates leukemogenesis as well as AML development. B ALKBH5 can specifically decrease the level of m6A in the 3’UTR of FOXM1 pre-mRNA, while As-FOXM1 promotes the interaction between ALKBH5 and FOXM1 pre-mRNA, which increases FOXM1 expression as well as GSC self-renewal and tumorigenesis. Similarly, As-ARHGAP5 can not only promote the transcription of ARHGAP5 but also induce METTL3 to deposit m6A modifications on ARHGAP5 mRNA, increasing the stability of ARHGAP5 mRNA in the cytoplasm and promoting the chemotherapy resistance of gastric cancer. Notably, HuR is involved in mRNA regulation in both the nucleus and cytoplasm. Another lncRNA, LCAT3, can be directly recognized by METTL3 and modified by m6A to increase stability and be upregulated, then it can bind to the far upstream elements of MYC together with FUBP1, leading to MYC activation and proliferation, invasion and metastasis of lung cancer cells. RNF168, Ring Finger Protein 168; BRD4, Bromodomain Containing 4; ELAVL1/HuR, ELAV Like RNA Binding Protein 1; DDX41, Dead box helicase 41; AML, Acute myeloid leukemia; TAD, Topologically associated domain; ALKBH5, AlkB Homolog 5; METTL3, Methyltransferase like 3; FOXM1, Forkhead Box M1; ARHGAP5, Rho GTPase Activating Protein 5; LCAT3, Lung Cancer Associated Transcript 3; FUBP1, Far Upstream Element Binding Protein 1