HDAC4 mediated LHPP deacetylation enhances its destabilization and promotes the proliferation and metastasis of nasopharyngeal carcinoma

by Selleckchem | Jun 18 2023

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.

Comments:

The study focuses on the role of LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) in nasopharyngeal carcinoma (NPC). The researchers found that LHPP is downregulated in NPC and acts as a tumor suppressor. They also discovered the regulatory mechanisms and functional implications of LHPP in NPC.

The study found that HDAC4 (histone deacetylase 4) is highly expressed in NPC cells and plays a role in promoting the proliferation and invasion of NPC cells through its interaction with LHPP. Specifically, HDAC4 deacetylates LHPP at a specific site (K6) and promotes LHPP degradation through TRIM21-mediated K48-linked ubiquitination. This suggests that HDAC4 negatively regulates LHPP levels in NPC cells.

Furthermore, the study found that LHPP inhibits the phosphorylation of a tyrosine kinase called TYK2, which in turn suppresses the activity of STAT1 (signal transducer and activator of transcription 1). This signaling pathway, involving TYK2 and STAT1, is known to play a role in cell proliferation and metastasis.

In vivo experiments demonstrated that knocking down HDAC4 or treating NPC with a small molecule inhibitor called Tasquinimod, which targets HDAC4, significantly inhibited the proliferation and metastasis of NPC. This effect was attributed to the upregulation of LHPP.

In summary, this research provides novel evidence regarding the involvement of the HDAC4/LHPP signaling axis in promoting the proliferation and metastasis of NPC through the upregulation of TYK2-STAT1 phosphorylation activation. These findings have implications for understanding the mechanisms underlying NPC metastasis and may offer potential intervention targets for future therapeutic strategies.