Oncogenic and tumor suppressor function of MEIS and associated factors

Abstract

MEIS proteins are historically associated with tumorigenesis, metastasis, and invasion in cancer. MEIS and associated PBX-HOX proteins may act as tumor suppressors or oncogenes in different cellular settings. Their expressions tend to be misregulated in various cancers. Bioinformatic analyses have suggested their upregulation in leukemia/lymphoma, thymoma, pancreas, glioma, and glioblastoma, and downregulation in cervical, uterine, rectum, and colon cancers. However, every cancer type includes, at least, a subtype with high MEIS expression. In addition, studies have highlighted that MEIS proteins and associated factors may function as diagnostic or therapeutic biomarkers for various diseases. Herein, MEIS proteins and associated factors in tumorigenesis are discussed with recent discoveries in addition to how they could be modulated by noncoding RNAs or newly developed small-molecule MEIS inhibitors.

Keywords: MEIS; MEIS inhibitors; cancer; small molecules.

Figure 1

Expression profile of Meis1-3, Pbx1-3, and a commonly associated Hoxa9 gene in cancer tissues when compared to adult healthy tissue. Cancer types could be separated into 3 groups based on the overall expression of Meis and its associated factors: upregulated, inconclusive, and downregulated groups of cancers. Note that these are the average of all of the subtypes in the indicated cancers. ACC: adrenocortical carcinoma, BLCA: bladder urothelial carcinoma, BRCA: breast invasive carcinoma, CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma COAD: colon adenocarcinoma, DLBC: lymphoid neoplasm diffuse large B-cell lymphoma, ESCA: esophageal carcinoma, GBM: glioblastoma multiforme, HNSC: head and neck squamous cell carcinoma, KICH: kidney chromophobe, KIRC: kidney renal clear cell carcinoma, KIRP: kidney renal papillary cell carcinoma, LAML: acute myeloid leukemia, LGG: brain lower grade glioma, LIHC: liver hepatocellular carcinoma, LUAD: lung adenocarcinoma, LUSC: lung squamous cell carcinoma, OV: ovarian serous cystadenocarcinoma, PAAD: pancreatic adenocarcinoma, PRAD: prostate adenocarcinoma, READ: rectum adenocarcinoma, SKCM: skin cutaneous melanoma, STAD: stomach adenocarcinoma, TGCT: testicular germ cell tumors, THCA: thyroid carcinoma, THYM: thymoma, UCEC: uterine corpus endometrial carcinoma, UCS: uterine carcinosarcoma.

Figure 2

Newly developed small-molecule MEIS inhibitors target HD-DNA interaction. Crystal structure of MEIS and HOXB13 homeodomains bound to DNA are shown.

Figure 3

Potent therapeutic approaches for MEIS+/High cancers. Meis1-3 and its cofactors are prominent oncogenic transcription factors. Various cancers could occur due to misregulation or mutations the MEIS transcription factors, which can be classified as Meis+/High and Meis–/Low. There are 2 types of potent targeted approaches for Meis+/High cancers: RNA-based methods and inhibitors/disrupters. While RNA-based methods inhibit the translation of Meis1-3 transcripts, the disruptors bind the MEIS protein in order to block its function or interaction with other cofactors. Thus, these approaches may cause the inhibition of tumor growth, induction of cancer cell apoptosis, and modulation of metabolic preference.