MUC1 基因在哺乳动物中进化，使屏障组织能够适应感染和损伤。 Paraspeckles 是 NEAT1 lncRNA 上因稳态丧失而形成的核体。 MUC1 与 NEAT1 或 paraspeckles 之间没有已知的交叉点。在这里，我们证明 MUC1-C 亚基在调节 NEAT1 表达中起着重要作用。 MUC1-C 通过 NF-κB 和 MYC 介导的机制诱导 NEAT1_1 和 NEAT1_2 亚型，从而激活 NEAT1 基因。 MUC1-C/MYC 信号传导还诱导 SFPQ、NONO 和 FUS RNA 结合蛋白 (RBP) 的表达，这些蛋白与 NEAT1_2 相关，并且是副斑点形成所必需的。 MUC1-C 通过招募 PBAF 染色质重塑复合物并增加各自调节区域的染色质可及性来整合 NEAT1 和 RBP 编码基因的激活。我们进一步证明 MUC1-C 和 NEAT1 形成一种自诱导途径，驱动常见基因组，从而对炎症和体内平衡丧失做出反应。具有功能意义的是，我们发现MUC1-C/NEAT1通路对于癌症干细胞（CSC）状态和抗癌耐药性具有重要意义。这些发现确定了 MUC1-C 在 NEAT1、RBP 和 paraspeckles 的调节中以前未被认识的作用，这些作用已被共同选择促进癌症进展。© 2024。作者。

The MUC1 gene evolved in mammals for adaptation of barrier tissues in response to infections and damage. Paraspeckles are nuclear bodies formed on the NEAT1 lncRNA in response to loss of homeostasis. There is no known intersection of MUC1 with NEAT1 or paraspeckles. Here, we demonstrate that the MUC1-C subunit plays an essential role in regulating NEAT1 expression. MUC1-C activates the NEAT1 gene with induction of the NEAT1_1 and NEAT1_2 isoforms by NF-κB- and MYC-mediated mechanisms. MUC1-C/MYC signaling also induces expression of the SFPQ, NONO and FUS RNA binding proteins (RBPs) that associate with NEAT1_2 and are necessary for paraspeckle formation. MUC1-C integrates activation of NEAT1 and RBP-encoding genes by recruiting the PBAF chromatin remodeling complex and increasing chromatin accessibility of their respective regulatory regions. We further demonstrate that MUC1-C and NEAT1 form an auto-inductive pathway that drives common sets of genes conferring responses to inflammation and loss of homeostasis. Of functional significance, we find that the MUC1-C/NEAT1 pathway is of importance for the cancer stem cell (CSC) state and anti-cancer drug resistance. These findings identify a previously unrecognized role for MUC1-C in the regulation of NEAT1, RBPs, and paraspeckles that has been co-opted in promoting cancer progression.© 2024. The Author(s).