MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity

Abstract

Localized prostate cancer develops very slowly in most men, with the androgen receptor (AR) and MYC transcription factors amongst the most well-characterized drivers of prostate tumorigenesis. Canonically, MYC up-regulation in luminal prostate cancer cells functions to oppose the terminally differentiating effects of AR. However, the effects of MYC up-regulation are pleiotropic and inconsistent with a poorly proliferative phenotype. Here we show that increased MYC expression and activity are associated with the down-regulation of MEIS1 , a HOX-family transcription factor. Using RNA-seq to profile a series of human prostate cancer specimens laser capture microdissected on the basis of MYC immunohistochemistry, MYC activity, and MEIS1 expression were inversely correlated. Knockdown of MYC expression in prostate cancer cells increased the expression of MEIS1 and increased the occupancy of MYC at the MEIS1 locus. Finally, we show in laser capture microdissected human prostate cancer samples and the prostate TCGA cohort that MEIS1 expression is inversely proportional to AR activity as well as HOXB13 , a known interacting protein of both AR and MEIS1. Collectively, our data demonstrate that elevated MYC in a subset of primary prostate cancers functions in a negative role in regulating MEIS1 expression, and that this down-regulation may contribute to MYC-driven development and progression.

Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer

“… 6 , 7 , 29 However, there is debate when it comes to the role of MEIS1 in solid tumors. The controversy is reflected in the potential tumor-suppress role of MEIS1 in prostate cancer 30 and clear cell renal cell carcinoma 31 and that depletion of MEIS1 as well as MEIS2 enhanced tumor growth by upregulating c-MYC and CD142, 7 but the oncogenic role of MEIS1 in glioma. 32 , 33 Therefore, the functions of MEIS1 in different solid tumors need to be further elaborated.…”

MEIS1 in Hematopoiesis and Cancer. How MEIS1-PBX Interaction Can Be Used in Therapy

“…Upregulation of MYC decreases MYC occupancy at the MEIS1 locus and leads to downregulation of MEIS1. On the other hand, knockdown of MYC activity leads to increased expression of MEIS1, following an increased occupancy of MYC at the MEIS1 locus [115]. In addition, in prostatic cancer tissues, statistically significant positive correlations between MYC and HOXB13 mRNA levels was observed [115], while an independent group confirmed that the tumor-suppressive activity of MEIS1 was dependent on HOXB13 [116].…”

MEIS1 and its potential as a cancer therapeutic target (Review)

“…MEIS1 has been associated with a variety of solid cancers, including prostate, non-small cell lung and gastric cancer, as well as clear cell renal cell carcinoma, esophageal squamous cell carcinoma, malignant peripheral nerve sheath tumors and Ewing sarcoma. The MYC-mediated downregulation of MEIS1 upregulates the androgen receptor (AR) to promote prostate cancer cell proliferation ( 64 ). AR transcription is inhibited by the overexpression of MEIS1 and is promoted by MEIS1 knockdown with small interfering RNA ( 49 ).…”