N 6 -Methyladenosine Modification of ANLN Enhances Hepatocellular Carcinoma Bone Metastasis.

Bones are categorized as the second most prevalent location of extra-hepatic metastasis in Hepatocellular Carcinoma (HCC), which is linked to an extremely poor prognosis due to limited therapeutic options. N6 -methyladenosine (m6 A) is a prominent modification involved in HCC, but the exact mechanisms on how m6 A modifications induce HCC bone metastases (BM) remain unclear. The key modulators responsible for the abundant m6 A RNA modification-induced HCC BM was found to be the METTL3 and YTHDF1 . The expression of Anillin actin-binding protein ( ANLN ) was dramatically higher in HCC with BM tissues, and its messenger RNA (mRNA) stability was enhanced via m6 A epitranscriptomic regulation by METTL3 and YTHDF1 . High METTL3 and YTHDF1 expression along with nuclear ANLN protein was clinically correlated with BM in HCC patients. Furthermore, HCC BM was attributed to over-expression of nuclear ANLN forming a transcriptional complex with SP1 which enhanced KIF2C transcriptional activity to activate the mTORC1 pathway, therefore increased the expression of RANKL and disproportionated RANKL-OPG expression in bone microenvironment leading to malignant neoplasms invade bone tissue. In addition, inhibition of ANLN m6 A modification by DZNeP attenuated HCC BM. This data provides meaningful understanding of the modulation and association of m6 A epitranscriptomic-regulated BM in HCC, and moreover, defines potentially valuable therapeutic targets.