HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration

Abstract

NAD+-dependent SIRT7 deacylase plays essential roles in ribosome biogenesis, stress response, genome integrity, metabolism and aging, while how it is transcriptionally regulated is still largely unclear. TGF-β signaling is highly conserved in multicellular organisms, regulating cell growth, cancer stemness, migration and invasion. Here, we demonstrate that histone deacetylase HDAC8 forms complex with SMAD3/4 heterotrimer and occupies SIRT7 promoter, wherein it deacetylates H4 and thus suppresses SIRT7 transcription. Treatment with HDAC8 inhibitor compromises TGF-β signaling via SIRT7-SMAD4 axis and consequently, inhibits lung metastasis and improves chemotherapy efficacy in breast cancer. Our data establish a regulatory feedback loop of TGF-β signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-β signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-β signaling related diseases.

RETRACTED ARTICLE: MYC-mediated upregulation of PNO1 promotes glioma tumorigenesis by activating THBS1/FAK/Akt signaling

“…[11][12][13] In addition, increasing evidence suggests that ribosome biogenesis plays important roles in cell growth and proliferation of many cancers, including glioma. [14][15][16][17] Thus, inhibiting ribosome biogenesis might provide new opportunities for cancer treatment. However, there are few studies of the ribosome-related function of PNO1 in cancers so far.…”

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…SMAD3 and -4 induce SIRT7 transcriptional repression by forming a complex with HDAC8. HDAC8 inhibition significantly suppresses TGF-β signaling via SMAD-SIRT7 axis, and as a consequence, attenuates lung metastases of breast cancer ( Tang et al, 2020 ). Class I HDACi 4SC-202 notably attenuates TGF-β-induced EMT ( Mishra et al, 2017 ).…”

A Translational Study of a Silicon Phthalocyanine Substituted with a Histone Deacetylase Inhibitor for Photodynamic Therapy

“… 54 HDAC8 overexpression, which is associated with poor prognosis in breast tumors, 55 has also been linked with increased proliferation and migration capacity before. 56 , 57 SiPc-HDACi decreased HDAC8 protein levels significantly in all treatment groups, while no significant difference between cell lines was observed. Since both HDAC6 and HDAC8 are known to increase cell motility, we next investigated the effect of SiPc-HDACi on CXCR4, CCR7, and CD44 protein levels, which are known to play major roles in cancer migration and invasion.…”