Targeting SETDB1 in cancer and immune regulation: Potential therapeutic strategies in cancer

Abstract

SET domain bifurcated histone lysine methyltransferase 1 (SETDB1/ESET), a pivotal H3K9 methyltransferase, has been extensively studied since its discovery over two decades ago. SETDB1 plays critical roles in immune regulation, including B cell maturation, T-cell activity modulation, and endogenous retrovirus (ERV) silencing. While essential for normal immune cell function, SETDB1 overexpression in cancer cells disrupts immune responses by suppressing tumor immunogenicity and facilitating immune evasion. This is achieved through the repression of anti-tumor immune cell production, ERV silencing, and interference with the type I interferon pathway leading to inhibiting immune checkpoint blockade (ICB) efficacy. Beyond its immunological implications, SETDB1 overexpression fosters tumor growth and metastasis via transcriptional silencing of tumor suppressor genes through histone regulation and activating oncogenic signaling by non-histone regulation. These multifaceted roles make SETDB1 an attractive epigenetic target for novel cancer therapies. This review explores SETDB1's dual function in immune regulation and tumor progression, emphasizing its potential in the development of innovative cancer treatments targeting epigenetic dysregulation and oncogenic signaling.

Keywords: SETDB1; cancer; endogenous retrovirus silencing; immune checkpoint blockage; methyltransferase.

FIGURE 1

SETDB1 structure and functional domains. SETDB1 contains a conserved SET domain, a variable I‐SET insert, and a unique triple TUDOR domain (TTD) that regulates its interaction with nucleosome. NES, nuclear export signal; NLS, nuclear localization signal.

FIGURE 2

SETDB1 activates important cancer signaling pathways through non‐histone protein methylation and/or association. (1) SETDB1 interacts with Akt upon growth factor engagement to its receptor and triggers methylation of Akt at K64, which recruits JMJD2A along with E3 ligase to induce K63‐lined ubiquitination of Akt leading to Akt membrane recruitment and activation. (2) SETDB1 interacts with p53 and triggers p53 dimethylation at K370, leading to increasing recognition and degradation of p53 by MDM2 and prevents apoptosis. (3) SETDB1 associates with Smad2/3 complex upon TGF‐β treatment to repress ANXA2 to regulate metastasis.

FIGURE 3

Current clinical drugs serve as SETDB1 antagonists. Mithramycin binds to the minor groove of GC‐rich DNA, displacing transcription factors like SP1 and SP3, thus leading to reduced SETDB1 expression. Paclitaxel treatment induces p53 expression, which suppresses SETDB1 promoter activity by binding directly to its proximal region leading to reduced SETDB1 expression.