PHF20L1: An Epigenetic Regulator in Cancer and Beyond

Abstract

Plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) is a novel epigenetic "reader" that specifically recognises histone post-translational modifications (PTMs) via its Tudor and PHD finger domains, thereby regulating chromatin remodelling, DNA damage repair, and oncogene transcriptional activation. This review comprehensively summarises the role of PHF20L1 in various cancers, including breast, ovarian, and colorectal cancers, as well as retinoblastomas, and elucidates its molecular mechanisms of action in cancer pathogenesis. Accumulating evidence indicates that PHF20L1 is upregulated in these malignancies and drives tumour progression by promoting proliferation, metastasis, and immune evasion. Furthermore, PHF20L1 orchestrates tumour-related gene expression by interacting with key epigenetic complexes. Given its unique structural features, we propose novel strategies for developing small-molecule inhibitors and combinatorial therapies, providing a theoretical basis for targeted epigenetic regulation for precision treatment. Future research should further investigate the molecular regulatory networks of PHF20L1 in different cancers and other human diseases and focus on developing specific small-molecule inhibitors to enable precision-targeted therapies.

Keywords: PHF20L1; cancer; epigenetic regulation; histone methylation; targeted therapy.

Figure 1

Versatile roles of PHF20L1 in cancer and epigenetic regulation. This schematic summarises PHF20L1’s oncogenic drivers in human cancers as well as its interactions with epigenetic markers and associated regulatory factors.

Figure 2

Domain-specific structural features of PHF20L1 underpin its epigenetic reader function. The structural architecture of PHF20L1, with a focus on its Tudor domains and PHD domain, reveals molecular mechanisms essential for mediating epigenetic regulation and driving cancer. The numbers indicate amino acid positions. Note: aa, amino acid.

Figure 3

The dual role of PHF20L1 in epigenetic regulation and chromatin remodelling. (A) PHF20L1 recognises histone modifications and recruits epigenetic complexes to promote chromatin condensation and transcriptional repression. (B) The intricate protein interaction network within the nucleus, which includes L3MBTL3-mediated recruitment of the CUL4A/B-DDB1-DCAF5 complex to regulate DNMT1 localisation and activity, PHF20L1-dependent modulation of SOX2, and coordinated ubiquitination/methylation processes, demonstrates the pivotal role of PHF20L1 as a molecular orchestrator in nuclear protein dynamics.

Figure 4

Comparative analysis of PHF20L1 expression in cancers and normal tissues. (A) The distribution of PHF20L1 expression levels across various tissues, highlighting its expression intensity in normal tissues. (B) PHF20L1 gene expression levels across various cancer types (measured in transcripts per million, TPM). Red and green dots represent PHF20L1 expression in tumour and normal tissues, respectively; error bars show standard deviation. (C) The alteration frequency of PHF20L1 in various cancers, based on TCGA data, includes mutations (green, point mutations or small insertions/deletions), structural variants (purple, large-scale chromosomal rearrangements), amplifications (red, increase in gene copy number), and deep deletions (blue, homozygous loss of both gene copies). The data presented in the figure were obtained from open-access platforms and visualised, including the Human Protein Atlas (https://www.proteinatlas.org/), GEPIA 2 (http://gepia2.cancer-pku.cn/#index, accessed on 25 April 2025), and cBioPortal (https://www.cbioportal.org/). All data were used in accordance with the terms of use specified by each database for academic and non-commercial purposes.

Figure 5

Expression and survival analysis of PHF20L1 in various cancers based on TCGA data. (A) PHF20L1 exhibited diverse expression patterns across various cancers and was significantly associated with overall patient survival. Heatmap illustrates PHF20L1 expression in different cancers, with red indicating high expression and blue indicating low expression. (B) The TCGA database revealed a notable correlation between PHF20L1 expression and overall patient survival. In sarcomas, adrenocortical carcinomas, and thyroid carcinomas, patients with high PHF20L1 expression showed markedly worse survival rates. The experimental data displayed in this figure were sourced from publicly accessible databases, including GEPIA 2 (http://gepia2.cancer-pku.cn/#index, accessed on 25 April 2025), in full compliance with the data usage policies and terms of service of the database.