Sun Xueshuo, Zhang Kun, Peng Xingzhi, Zhou Peijun, Qu Chunhui, Yang Lifang, Shen Liangfang
Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410078, China.
Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410078, China; Cancer Research Institute, School of Basic Medicine Science, Central South University, Changsha, 410078, China.
Cancer Lett. 2023 May 28;562:216158. doi: 10.1016/j.canlet.2023.216158. Epub 2023 Apr 5.
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.
研究表明，乙酰化修饰在肿瘤增殖和转移中起重要作用。磷赖氨酸磷组氨酸无机焦磷酸磷酸酶（LHPP）在某些肿瘤中表达下调，具有肿瘤抑制作用。然而，LHPP在鼻咽癌（NPC）中的表达调控及其功能仍不清楚。在本研究中，我们发现LHPP在NPC中表达下调，过表达LHPP可抑制NPC细胞的增殖和侵袭。机制上，HDAC4使LHPP的K6位点去乙酰化，并通过TRIM21介导的K48连接的泛素化促进LHPP的降解。证实HDAC4在NPC细胞中高表达，并通过LHPP促进NPC细胞的增殖和侵袭。进一步研究发现，LHPP可抑制酪氨酸激酶TYK2的磷酸化，从而抑制STAT1的活性。在体内，敲低HDAC4或用靶向HDAC4的小分子抑制剂他司莫德治疗可通过上调LHPP显著抑制NPC的增殖和转移。总之，我们的研究结果表明，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。本研究将为NPC转移提供新的证据和干预靶点。
