研究表明，乙酰化修饰在肿瘤增殖和转移中起重要作用。某些肿瘤下调天然抑癌基因磷酸溶网状组织酸磷酸酯酶（LHPP）作为抑制肿瘤生长的角色。然而，LHPP表达的调节及其在鼻咽癌（NPC）中的功能仍不清楚。在本研究中，我们发现LHPP在NPC中下调，LHPP的过表达抑制NPC细胞的增殖和侵袭。机制上，HDAC4在K6位点上去乙酰化LHPP并促进LHPP通过TRIM21介导的K48-连锁泛素化降解。确认HDAC4在NPC细胞中高表达，并通过LHPP促进NPC细胞的增殖和侵袭。进一步的研究发现LHPP可以抑制酪氨酸激酶TYK2的磷酸化，从而抑制STAT1的活性。在体内，HDAC4敲低或用靶向HDAC4的小分子抑制剂Tasquinimod治疗可以通过上调LHPP来显著抑制NPC的增殖和转移。总之，我们的发现证明HDAC4/LHPP信号轴通过上调TYK2-STAT1磷酸化激活促进NPC的增殖和转移。这项研究将为NPC转移提供新的证据和干预靶点。Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Studies have shown that acetylation modification plays an important role in tumor proliferation and metastasis. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is downregulated in certain tumors, as a tumor suppressor role. However, the regulation of LHPP expression and its function in nasopharyngeal carcinoma (NPC) remain unclear. In the present study, we found that LHPP was downregulated in NPC, and overexpression of LHPP inhibited the proliferation and invasion of NPC cells. Mechanistically, HDAC4 deacetylated LHPP at K6 and promoted the degradation of LHPP through TRIM21 mediated K48-linked ubiquitination. HDAC4 was confirmed to be highly expressed in NPC cells and promoted the proliferation and invasion of NPC cells through LHPP. Further research found that LHPP could inhibit the phosphorylation of tyrosine kinase TYK2, thereby inhibiting the activity of STAT1. In vivo, knockdown of HDAC4 or treatment with small molecule inhibitor Tasquinimod targeting HDAC4 could significantly inhibit the proliferation and metastasis of NPC by upregulating LHPP. In conclusion, our finding demonstrated that HDAC4/LHPP signal axis promotes the proliferation and metastasis of NPC through upregulating TYK2-STAT1 phosphorylation activation. This research will provide novel evidence and intervention targets for NPC metastasis.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.