HDAC11 interacts with the NuRD (MTA3) complex to transcriptionally suppress TGFβ1 expression and inhibit hepatocellular carcinoma metastasis.

Abstract

Hepatocellular carcinoma (HCC) is a leading global health concern, recognized for its complex pathogenesis and high mortality rates. The metastatic progression of HCC, considered the terminal event in tumor development, plays a pivotal role in determining patient prognosis, with metastasis being a key factor in poor survival outcomes.HDAC11 was found to be highly expressed in HCC tissues, with its elevated expression significantly correlating with poor patient survival. Both in vitro and in vivo experiments demonstrated that silencing HDAC11 led to a marked reduction in HCC cell proliferation. Interestingly, HDAC11 knockdown also resulted in a substantial increase in the metastatic potential of HCC cells. Mass spectrometry analysis revealed that HDAC11 interacts with the NuRD (MTA3) complex. Consistently, immunoprecipitation and GST pull-down assays demonstrated that the N-terminal region of HDAC11 directly binds to MTA3. Moreover, transcriptomic analysis indicated that HDAC11 represses TGFB1 transcription, thereby inhibiting HCC metastasis. The enhanced metastatic phenotype induced by HDAC11 silencing was reversed upon concurrent down-regulation of TGFB1. Moreover, nanoparticles encapsulating both HDAC11 and TGF-β1 inhibitors effectively suppressed HCC cell proliferation and metastasis. This research elucidates the molecular mechanism by which HDAC11 inhibits metastasis and provides an effective strategy to mitigate the side effects associated with HDAC11 inhibition, offering novel insights and approaches for the precision treatment of HCC.