Targeting the 'garbage-bin' to fight cancer: HDAC6 inhibitor WT161 has an anti-tumor effect on osteosarcoma and synergistically interacts with 5-FU.

Consolato M Sergi

doi:10.1042/bsr20210952

Abstract

An imbalance between protein aggregation and protein degradation may induce ‘stress’ in the functionality of the endoplasmic reticulum (ER). There are quality control (QC) mechanisms to minimize misfolding and to eliminate misfolded proteins before aggregation becomes lethal for the cell. Proper protein folding and maturation is one of the crucial functions of the ER. Chaperones of the ER and folding enzymes guarantee correct conformational maturation of emerging secretory proteins. Histone deacetylase (HDAC) 6 (HDAC6) is a masterpiece coordinating the cell response to protein aggregate formation. The balance between HDAC6 and its partner Valosin-containing protein/p97 determines the fate of polyubiquitinated misfolded proteins. WT161 is a terrific, selective, and bioavailable HDAC6 inhibitor. WT161 selectively inhibits HDAC6 and adequately increases levels of acetylated α-tubulin. This compound induces accumulation of acetylated tubulin and cytotoxicity in multiple myeloma (MM) cells. In this journal, Sun et al. (Biosci. Rep. 41, DOI: 10.1042/BSR20203905) identified that WT161 suppresses the cell growth of osteosarcoma cells. This discovery opens the door to future chemotherapeutic regimens of this bone neoplasm.

Highlights

The synthesis of proteins is not a smooth road, but each protein undergoes a series of pitfalls to become fully functional
There are quality control (QC) mechanisms to minimize misfolding and to eliminate misfolded proteins before aggregation becomes lethal for the cell
endoplasmic reticulum (ER) chaperones are critical to many aspects of this crucial ER function, whether in protein folding modes, as calcium binders, as sensors of stress such as the unfolded protein response, or due to cell-surface localization or extracellular release, as immune modulators [9]

Summary

Introduction

The synthesis of proteins is not a smooth road, but each protein undergoes a series of pitfalls to become fully functional. ER chaperones are critical to many aspects of this crucial ER function, whether in protein folding modes, as calcium binders, as sensors of stress such as the unfolded protein response, or due to cell-surface localization or extracellular release, as immune modulators [9]. Some scarcity of key components can determine imbalances between protein aggregation and degradation in the proteasome, which remains crucial as the cellular machinery involved in the degradation of aging proteins and autophagy inhibition [10].

Results

Conclusion