Question

Why is the existence of the HOXB-AS3 peptide a contradiction to previous knowledge?

Answer 1

HOXB-AS3 (HOXB Cluster Antisense RNA 3) is an RNA Gene, and belongs to lncRNA class and  encodes a highly conserved 53-aa peptide called HOXB-AS3 .

Previous studies suggest that HOXB-AS3 is tumour suppresor and it's downregulation suppresses colon cancer growth. Mechanistically, the HOXB-AS3 peptide competitively binds to the ariginine residues in RGG motif of hnRNP A1 and antagonizes the hnRNP A1-mediated regulation of pyruvate kinase M (PKM) splicing by blocking the binding of the ariginine residues in RGG motif of hnRNP A1 to the sequences flanking PKM exon 9, ensuring the formation of lower PKM2 and suppressing glucose metabolism reprogramming.( Reference -doi: 10.1016/j.molcel.2017.09.01)

  HOXB-AS3 inhibits cancer cell proliferation, invasion, and metastasis and suppresses tumor growth. HOXB-AS3 downregulates PKM2 but upregulates PKM1. Therefore, HOXB-AS3 inhibits aerobic glycolysis and increases lactic acid production in CRC cells. The loss of HOXB-AS3 is a key oncogenic event in CRC metabolic reprogramming. (Dimitrios et al;2019)

Recent study reports that higher expression of HOXB-AS3 peptide promotes the proliferation of myeloid cells through upregulating the expressions of a set of genes critical for cell cycle progression and DNA replication and responsible for myeloid malignancies in case of acute myeloid leukemia and myelodysplastic syndrome.

• Reference-(Huai-Hsuan Huang et al; 2019)

The seemingly contradiction between this previous study and recent  findings are likely due to the different variants of HOXB-AS3 used.  The previous study investigated exclusively HOXB-AS3 variant 1, and the small peptide is encoded from the last two exons of this variant . However, in leukemia cell lines, variant 1 is expressed at a very low level, and the majority of HOXB-AS3 transcripts are variants 2/3/5 and variant, variant 2 was selected for the overexpression studies and results are consistent with the derived conclusions in this study.

Therefore, the current and previous studies suggest the existence of variant-specific functions of HOXB-AS3